Indolyl-pyridone derivatives having checkpoint kinase 1 inhibitory activity

ABSTRACT

Compounds of formula (I) have checkpoint kinase 1 (CHK1) inhibitory activity: 
                         
wherein R 1 , R 2 , R 5  and R 6  are independently selected from hydrogen, hydroxy, methyl, trifluoromethyl, hydroxymethyl, methoxy, trifluoromethoxy, methylamino and dimethylamino; R 3 , and R 4  are independently selected from hydrogen, hydroxy, C 1 -C 3  alkyl, fluoro-(C 1 -C 3 )-alkyl, hydroxy-(C 1 -C 3 )-alkyl, C 1 -C 3  alkoxy, fluoro-(C 1 -C 3 )-alkoxy, hydroxy-(C 1 -C 3 )-alkoxy, —N(R 11 )—R 12 , -Alk-N(R 11 )—R 12 , —O-Alk-N(R 11 )—R 12 , —C(═O)OH, carboxy-(C 1 -C 3 )-alkyl, or —C(═O)—NH—R 13 ; Alk is a straight or branched chain divalent C 1 -C 6  alkylene radical; R 7  and R 8  are independently selected from hydrogen, hydroxy, or C 1 -C 3  alkoxy; X is a straight chain divalent C 1 -C 3  alkylene radical, optionally substituted on one or more carbons by R 9  and/or R 10 ; W is selected from —C(═O)—N(—R 16 )— or —N(—R 17 )—C(═O)—; Y is hydrogen, C 1 -C 3  alkyl, C 1 -C 3  alkoxy, or halo; and Q is selected from optionally substituted phenyl, optionally substituted cyclohexyl, or an optionally substituted 6-membered monocyclic heteroaryl ring.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 12/812,791 filed Sep. 23, 2010, now allowed, which is a NationalStage application of co-pending PCT application PCT/GB2009/000149 filedJan. 20, 2009, which claims the benefit of Great Britain applicationnumber 0801090.2 filed Jan. 22, 2008 and Great Britain applicationnumber 0818695.9 filed Oct. 11, 2008. These applications areincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

This invention relates to indolyl-pyridone derivatives having checkpointkinase 1 (CHK1) inhibitory activity, to the use of such compounds inmedicine, particularly in relation to the treatment of cancer, via theinhibition of aberrant cell proliferation, and to pharmaceuticalcompositions containing such compounds.

BACKGROUND OF THE INVENTION

Many standard cancer chemotherapeutic agents act primarily through theirability to induce DNA damage causing tumor growth inhibition. However,these agents cause cell cycle arrest by induction of checkpoints ateither S-phase or G2-M boundary. The G2 arrest allows the cell time torepair the damaged DNA before entering mitosis. CHK1 and an unrelatedserine/threonine kinase, CHK2, play a central role in arresting the cellcycle at the G2-M boundary (O'Connell et al EMBO J (1997) vol 16 p545-554). CHK1/2 induce this checkpoint by phosphorylating serine 216 ofthe CDC25 phosphatase, inhibiting the removal of two inactivatingphosphates on cyclin dependent kinases (CDKs) (Zheng et al Nature (1998)vol 395 p 507-510). Another overlapping pathway mediated by p53 alsoelicits cycle arrest in response to DNA-damage. However, p53 ismutationally inactivated in many cancers, resulting in a partialdeficiency in their ability to initiate a DNA-repair response. If CHK1activity is also inhibited in p53-negative cancers, all ability toarrest and repair DNA in response to DNA-damage is removed resulting inmitotic catastrophe and enhancing the effect of the DNA damaging agents(Konarias et al Oncogene (2001) vol 20 p 7453-7463, Bunch and EastmanClin. Can. Res. (1996) vol 2 p 791-797, Tenzer and Pruschy Curr. MedChem (2003) vol 3 p 35-46). In contrast, normal cells would berelatively unaffected due to retention of a competent p53-mediatedcell-cycle arrest pathway. The inhibition of DNA damage checkpoints istherefore expected to sensitise aberrantly proliferating cells to DNAdamaging agents. Such sensitization is in turn expected to increase thetherapeutic index of such chemotherapeutic agents or ionizing radiation.(Clary, D.O. Inhibition of Chk kinases in a leukemia model abrogates DNAdamage checkpoints and promotes mitotic catastrophe. Proc Am AssocCancer Res (AACR) 2007, 48: Abst 5385) Therefore it is expected thatefficacious inhibitors of CHK1 will lead to a corresponding Improvementin the efficacy of current DNA-damage inducing chemotherapeutic regimens(Sausville et al, J. Clinical Oncology (2001) vol 19 p 2319-2333). Anumber of putative CHK1 inhibitors are currently in phase I clinicaltrials including XL-844 (a dual CHK1/CHK2 inhibitor for the treatment oflymphoma and solid tumours), PF 00477736 (Phase I Study of PF-00477736with gemcitabine in patients with advanced solid malignancies) & AZD7762(Phase I open label multi center dose escalation study to assess safetytolerability and pharmacokinetics of AZD7762 administered as a singleintravenous agent and in combo with weekly standard dose gemcitabine inpatients with advanced solid malignancies). Thus, there remains an unmetmedical need for low molecular weight CHK1 inhibitors withpharmacokinetic and pharmacodynamic properties making them suitable foruse as pharmaceutical agents. The object of the present invention is toprovide such pharmaceutical agents and treatments.

It has now been found that certain indolyl-pyridone derivatives showefficacy as CHK1 inhibitors.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to a class of substituted indolyl-pyridonecompounds useful as CHK1 inhibitors, for example, for the treatment ofcancer. A core indolyl-pyridone template, with substitution on thepyridone portion by a substituted-pyrazolyl amido-linked group areprinciple characterising features of the compounds with which theinvention is concerned.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the In vivo potentiation results of the compound of Example20 in combination with gemcitabine.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, there is provided a compound offormula (I) or a pharmaceutically acceptable salt thereof:

whereinR₁, R₂, R₅ and R₆ are independently selected from hydrogen, hydroxy,methyl, trifluoromethyl, hydroxymethyl, methoxy, trifluoromethoxy,methylamino and dimethylamino;R₃ and R₄, are independently selected from hydrogen, hydroxy, C₁-C₃alkyl, fluoro-(C₁-C₃)-alkyl, hydroxy-(C₁-C₃)-alkyl, C₁-C₃ alkoxy,fluoro-(C₁-C₃)-alkoxy, hydroxy-(C₁-C₃)-alkoxy, —N(R₁₁)—R₁₂,-Alk-N(R₁₁)—R₁₂, —O-Alk-N(R₁₁)—R₁₂, —C(═O)OH, carboxy-(C₁-C₃)-alkyl, or—C(═O)—NH—R₁₃;Alk is a straight or branched chain divalent C₁-C₆ alkylene radical;R₇ and R₈ are independently selected from hydrogen, hydroxy, or C₁-C₃alkoxy;X is a straight chain divalent C₁-C₃ alkylene radical, optionallysubstituted on one or more carbons by R₉ and/or R₁₀;R₉ and R₁₀ are independently selected from methyl, hydroxy, or fluoro;R₁₁ is hydrogen, C₁-C₃ alkyl, or fluoro-(C₁-C₃)-alkyl, andR₁₂ is C₁-C₃ alkyl or hydroxy-(C₁-C₆)-alkyl, either of which may beoptionally substituted on the alkyl portion by phenyl, C₁-C₃alkoxy-(C₁-C₃)-alkyl, halo-(C₁-C₄)-alkyl, C₃-C₆ cycloalkyl,methylsulfonyl-(C₁-C₃)-alkyl or —N(R₁₈)—R₁₉;R₁₃ is hydrogen, C₁-C₃ alkyl, fluoro-(C₁-C₃)-alkyl, or a radical offormula -Alk-N(R₁₄)—R₁₅;R₁₄ and R₁₅ are independently selected from hydrogen, C₁-C₃ alkyl, orfluoro-(C₁-C₃)-alkyl;or R₁₁ and R₁₂, or R₁₄ and R₁₅, together with the nitrogen atom to whichthey are respectively attached, form an optionally substituted, 4- to6-membered, monocyclic heterocyclic ring having no more than threeadditional heteroatoms independently selected from oxygen, sulphur andnitrogen;W is selected from —C(═O)—N(—R₁₆)— or —N(—R₁₇)—C(═O)—;R₁₆ or R₁₇ is selected from hydrogen, C₁-C₃ alkyl, orfluoro-(C₁-C₃)-alkyl;R₁₈ and R₁₉ are selected from hydrogen, C₁-C₃ alkyl, orfluoro-(C₁-C₃)-alkyl, or R₁₈ and R₁₉ together with the nitrogen atom towhich they are respectively attached, form an optionally substituted, 4-to 6-membered, monocyclic heterocyclic ring having no more than threeadditional heteroatoms independently selected from oxygen, sulphur andnitrogen;Y is hydrogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, or halo; andQ is selected from optionally substituted phenyl, optionally substitutedcyclohexyl, or an optionally substituted 6-membered monocyclicheteroaryl ring.

The active compounds of formula (I) are inhibitors of CHK1, and areuseful for the treatment, prevention and suppression of a proliferativedisease such as cancer in combination with radiotherapy or chemotherapy.

According to a further embodiment of the present invention there isprovided the use of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament forenhancing a therapeutic effect of radiation or chemotherapy in thetreatment of cancer.

According to a further embodiment of the present invention there isprovided a method of treatment of cancer comprising administration to asubject in need of such treatment an effective dose of the compound offormula (I), or a pharmaceutically acceptable salt thereof.

According to a further embodiment of the present invention there isprovided a pharmaceutical composition comprising a compound of formula(I), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

TERMINOLOGY

As used herein, the term “(C_(a)-C_(b))alkyl” wherein a and b areintegers refers to a straight or branched chain alkyl radical havingfrom a to b carbon atoms. Thus when a is 1 and b is 6, for example, theterm includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl and n-hexyl.

As used herein the term “divalent (C_(a)-C_(b))alkylene radical” whereina and b are integers refers to a saturated hydrocarbon chain having froma to b carbon atoms and two unsatisfied valences, such as —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂— and —CH₂C(CH₃)₂CH₂—. For theavoidance of doubt, it is to be understood that a divalent branchedchain (C_(a)-C_(b))alkylene radical includes those wherein one of thecarbons of the hydrocarbon chain is a ring carbon of a cycloalkyl ring(ie is a spiro centre), such as those of formulae (II):

As used herein, the term “fluoro-(C_(a)-C_(b))-alkyl” wherein a and bare integers refers to a straight or branched chain alkyl radical havingfrom a to b carbon atoms substituted by one or more fluoro atoms. Theterm includes, for example, fluoromethyl, difluoromethyl andtrifluoromethyl.

As used herein the term “cycloalkyl” refers to a saturated carbocyclicradical having from 3-8 carbon atoms and includes, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

As used herein the term “carbocyclic” refers to a mono- or bi-cyclicradical whose ring atoms are all carbon, and includes monocyclic aryl,cycloalkyl, and cycloalkenyl radicals, provided that no single ringpresent has more than 8 ring members. A “carbocyclic” group includes amono-bridged or multiply-bridged cyclic alkyl group.

As used herein the term “aryl” refers to a mono-, bi- or tri-cycliccarbocyclic aromatic radical. Illustrative of such radicals are phenyl,biphenyl and napthyl.

As used herein the term “heteroaryl” refers to a mono-, bi- ortri-cyclic aromatic radical containing one or more heteroatoms selectedfrom S, N and O. Illustrative of such radicals are thienyl, benzthienyl,furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl,benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl,benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl,benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.

As used herein the unqualified term “heterocyclyl” or “heterocyclic”includes “heteroaryl” as defined above, and in particular refers to amono-, bi- or tri-cyclic non-aromatic radical containing one or moreheteroatoms selected from S, N and O, to groups consisting of amonocyclic non-aromatic radical containing one or more such heteroatomswhich is covalently linked to another such radical or to a monocycliccarbocyclic radical, and to a mono-, bi- or tri-cyclic non-aromaticradical containing one or more heteroatoms selected from S, N and Owhich is mono-bridged or multiply-bridged. Illustrative of such radicalsare pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl,pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl,benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl,ethylenedioxyphenyl, maleimido and succinimido groups.

Unless otherwise specified in the context in which it occurs, the term“substituted” as applied to any moiety herein means substituted with atleast one substituent, for example selected from (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto,mercapto(C₁-C₆)alkyl, (C₁-C₆)alkylthio, halo (including fluoro andchloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo,phenyl, —COOH, —COOR^(A), —COR^(A), —SO₂R^(A), —CONH₂, —SO₂NH₂,—CONHR^(A), —SO₂NHR^(A), —CONR^(A)R^(B), —SO₂NR^(A)R^(B), —NH₂,—NHR^(A), —NR^(A)R^(B), —OCONH₂, —OCONHR^(A), —OCONR^(A)R^(B),—NHCOR^(A), —NHCOOR^(A), —NR^(B)COOR^(A), —NHSO₂OR^(A),—NR^(B)SO₂OR^(A), —NHCONH₂, —NR^(A)CONH₂, —NHCONHR^(B),—NR^(A)CONHR^(B), —NHCONR^(A)R^(B), or —NR^(A)CONR^(A)R^(B) whereinR^(A) and R^(B) are independently a (C₁-C₆)alkyl group, or R^(A) andR^(B) when attached to the same nitrogen may form a cyclic amino ringsuch as a morpholinyl, piperidinyl or piperazinyl ring. An “optionalsubstituent” or “substituent” may be one of the foregoing substituentgroups.

As used herein the term “salt” includes base addition, acid addition andquaternary salts. Compounds of the invention which are acidic can formsalts, including pharmaceutically or veterinarily acceptable salts, withbases such as alkali metal hydroxides, e.g. sodium and potassiumhydroxides, alkaline earth metal hydroxides e.g. calcium, barium andmagnesium hydroxides, with organic bases e.g. N-ethyl piperidine,dibenzylamine and the like. Those compounds (I) which are basic can formsalts, including pharmaceutically or veterinarily acceptable salts withinorganic acids, e.g. with hydrohalic acids such as hydrochloric orhydrobromic acids, sulphuric acid, nitric acid or phosphoric acid andthe like, and with organic acids e.g. with acetic, tartaric, succinic,fumaric, maleic, malic, salicylic, citric, methanesulphonic andp-toluene sulphonic acids and the like.

For a review on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Compounds of the invention are expected to be isolatable as hydrates andsolvates. The term ‘solvate’ is used herein to describe a molecularcomplex comprising the compound of the invention and a stoichiometricamount of one or more pharmaceutically acceptable solvent molecules, forexample, ethanol. The term ‘hydrate’ is employed when said solvent iswater. Any reference herein to a compound of formula(I) is to beunderstood as including such hydrates and solvates.

Compounds with which the invention is concerned which may exist in oneor more stereoisomeric form, because of the presence of asymmetric atomsor rotational restrictions, can exist as a number of stereoisomers withR or S stereochemistry at each chiral centre or as atropisomeres with Ror S stereochemistry at each chiral axis. The invention includes allsuch enantiomers and diastereoisomers and mixtures thereof.

So-called ‘pro-drugs’ of the compounds of formula (I) are also withinthe scope of the invention. Thus certain derivatives of compounds offormula (I) which may have little or no pharmacological activitythemselves can, when administered into or onto the body, be convertedinto compounds of formula (I) having the desired activity, for example,by hydrolytic cleavage. Such derivatives are referred to as ‘prodrugs’.Further information on the use of prodrugs may be found in Pro-drugs asNovel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W.Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987(ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula (I) with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985).

Also included within the scope of the invention are metabolites ofcompounds of formula (I), that is, compounds formed in vivo uponadministration of the drug. Some examples of metabolites include

(i) where the compound of formula (I) contains a methyl group, anhydroxymethyl derivative thereof (—CH₃→—CH₂OH):

(ii) where the compound of formula (I) contains an alkoxy group, anhydroxy derivative thereof (—OR→—OH),

(iii) where the compound of formula (I) contains a tertiary amino group,a secondary amino derivative thereof (—NR¹R²→—NHR¹ or —NHR²),

(iv) where the compound of formula (I) contains a secondary amino group,a primary derivative thereof (—NHR¹→—NH₂),

(v) where the compound of formula (I) contains a phenyl moiety, a phenolderivative thereof (-Ph→-PhOH), and

(vi) where the compound of formula (I) contains an amide group, acarboxylic acid derivative thereof (—CONH₂→COOH).

Variable substituents present in compounds (I) will now be furtherdescribed. It is to be understood in the further description that anydisclosed substituent or substituent class may be present in anycombination with any of the other disclosed substituent classes.Specific examples of the variable substituents include those present inthe compounds of the Examples herein.

The Groups R₁, R₂, R₅ and R₆

R₁, R₂, R₅ and R₆ are independently selected from hydrogen, or smallsubstituents such as hydroxy, methyl, trifluoromethyl, hydroxymethyl,methoxy, trifluoromethoxy, methylamino and dimethylamino. Currently itis preferred that R₁, R₂, R₅ and R₆ are each hydrogen.

The Groups R₃ and R₄

R₃ and R₄ are hydrogen, hydroxy, C₁-C₃ alkyl, fluoro-(C₁-C₃)-alkyl,hydroxy-(C₁-C₃)-alkyl, C₁-C₃ alkoxy, fluoro-(C₁-C₃)-alkoxy,hydroxy-(C₁-C₃)-alkoxy, -Alk-N(R₁₁)—R₁₂, —O-Alk-N(R₁₁)—R₁₂, —C(═O)OH,carboxy-(C₁-C₃)-alkyl, or —C(═O)—NH—R₁₃.

In some embodiments of the invention, one of R₃ and R₄ is hydrogen andthe other is selected from —N(R₁₁)—R₁₂, -Alk-N(R₁₁)—R₁₂, and—O-Alk-N(R₁₁)—R₁₂, especially the latter two. Currently it is preferredthat R₄ be hydrogen. R₁₁ and R₁₂ together with the nitrogen atom towhich they are attached, may form an optionally substituted, 4- to6-membered, monocyclic heterocyclic ring having no more than threeadditional heteroatoms independently selected from oxygen, sulphur andnitrogen. Preferred structures include those wherein R₁₁ and R₁₂together with the nitrogen atom to which they are attached form anazetidine, pyrrolidine, piperidine, morpholine, or piperazine ring,optionally substituted by C₁-C₃ alkyl, hydroxy-(C₁-C₃)-alkyl, fluoro, orhydroxy. Particularly preferred are those compounds wherein R₁₁ and R₁₂together with the nitrogen atom to which they are attached form1-hydroxy-azetidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl,morpholin-4-yl, piperazin-1-yl, 1-methyl-piperidin-4-yl,1-fluoro-piperidin-4-yl, 1-hydroxy-piperidin-4-yl,1-(hydroxymethyl)piperidin-4-yl, or 1-methyl-piperazin-4-yl. In thissubclass Alk may be, for example C₁-C₆ alkylene, preferably methylene,or ethylene. In this subclass Alk may be, for example —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂— or —CH₂CH(CH₃)CH₂— or a divalent branched chain alkyleneradical —CH₂C(CH₃)₂CH₂— or of formula (II):

In other embodiments of the invention, one of R₃ and R₄ is hydrogen andthe other is selected from —N(R₁₁)—R₁₂, -Alk-N(R₁₁)—R₁₂, and—O-Alk-N(R₁₁)—R₁₂, especially the latter two, wherein R₁₁ and R₁₂ areindependently selected from C₁-C₃ alkyl, for example methyl and ethyl,or R₁₁ is C₁-C₃ alkyl, for example methyl or ethyl and R₁₂ is—N(R₁₈)—R₁₉ wherein R₁₈ and R₁₉ are independently selected from C₁-C₃alkyl, for example methyl and ethyl. In this subclass also Alk may be,for example —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂CH(CH₃)CH₂— orpreferably a divalent branched chain alkylene radical —CH₂C(CH₃)₂CH₂— orof formula (II):

In other embodiments of the invention, one of R₃ and R₄ is hydrogen andthe other is selected from —N(R₁₁)—R₁₂, -Alk-N(R₁₁)—R₁₂, or—O-Alk-N(R₁₁)—R₁₂, wherein R₁₁ is hydrogen or C₁-C₃ alkyl, particularlymethyl or ethyl, and R₁₂ is hydroxy-(C₁-C₆)-alkyl, such as2-hydroxy-ethyl. In this subclass also Alk may be, for example —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂CH(CH₃)CH₂— or preferably a divalentbranched chain alkylene radical —CH₂C(CH₃)₂CH₂— or of formula (II):

The Group Y

Y is hydrogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, or halo. Presently, it ispreferred that Y is hydrogen, methyl, methoxy, or halo. Particularlypreferred are those compounds wherein Y is hydrogen or methyl.

The Group W

W is selected from —C(═O)—N(—R₁₆)— or —N(—R₁₇)—C(═O)—. R₁₆ and R₁₇ areselected from hydrogen C₁-C₃ alkyl such as methyl andfluoro-(C₁-C₃)-alkyl such as trifluoromethyl. Preferred structuresinclude those wherein W is —C(═O)—NH— (ie where the nitrogen is linkedto the pyrazole ring, or —NH—C(═O)— (ie where the carbonyl group islinked to the pyrazole ring), particularly the latter.

The Radicals R₇ and R₈

R₇ and R₈ are independently selected from hydrogen, hydroxy, or C₁-C₃alkoxy. Preferred structures include those wherein R₇ and R₈ areindependently selected from hydrogen, hydroxy, or methoxy. Particularlypreferred cases are wherein one or both of R₇ and R₈ is/are hydrogen.

The Divalent Radical X

X is a straight chain divalent C₁-C₃ alkylene radical, optionallysubstituted on one or more carbons by R₉ and/or R₁₀. R₉ and R₁₀ areindependently selected from methyl, hydroxy, or fluoro. Currently, it ispreferred that both R₉ and R₁₀ when present are methyl. For example, Xmay be —CH₂—, —CH(CH₃)— or —C(CH₃)₂—.

The Group Q

Q is selected from optionally substituted phenyl, optionally substitutedcyclohexyl, or an optionally substituted 6-membered monocyclicheteroaryl ring.

In a subclass of compounds with which the invention is concerned, Q isunsubstituted or substituted phenyl. Unsubstituted phenyl is currentlypreferred, but when substituents are present the phenyl ring may besubstituted by no more than two substituents independently selected fromC₁-C₃ alkyl, halo-(C₁-C₃)alkyl, C₁-C₃ alkoxy, halo, or cyano. Preferredsubstituents are methyl, trifluoromethyl, methoxy, fluoro, chloro, orcyano. Preferred structures include those wherein Q is 2-methyl-phenyl,3-methyl-phenyl, 4-methyl-phenyl, 3-trifluoromethyl-phenyl,4-trifluoromethyl-phenyl, 4-methoxy-phenyl, 2-fluoro-phenyl,3-fluoro-phenyl, 4-fluoro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl,3-cyano-phenyl, 4-cyano-phenyl, 3,4-difluoro-phenyl,3,5-difluoro-phenyl, or 3-fluoro-4-methyl-phenyl.

In another subclass of compounds with which the invention is concerned,Q is optionally substituted cyclohexyl.

In yet a further subclass of compounds with which the invention isconcerned, Q is an optionally substituted 6-membered monocyclicheteroaryl ring, preferably pyridyl, particularly pyrid-3-yl orpyrid-4-yl.

Currently, it is preferred that Q is phenyl, 3-methyl-phenyl,4-methyl-phenyl, 3-trifluoromethyl-phenyl, 3-fluoro-phenyl,4-fluoro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3,4-difluoro-phenyl,or 3,5-difluoro-phenyl, particularly phenyl, 4-methyl-phenyl, or4-chloro-phenyl.

In a currently preferred subclass of compounds of formula (I) of theinvention, R₁, R₂, R₄, R₅, R₆, R₇ and R₅ are each hydrogen; Y ishydrogen or methyl; W is —NH—C(═O)— wherein the carbonyl group is linkedto the pyrazole ring; R₃ is -Alk-N(R₁₁)—R₁₂, or —O-Alk-N(R₁₁)—R₁₂; R₁₁and R₁₂ together with the nitrogen atom to which they are attached forman optionally substituted, 5- to 6-membered, monocyclic heterocyclicring having no more than three additional heteroatoms independentlyselected from oxygen, sulphur and nitrogen. or R₁₁ and R₁₂ areindependently selected from methyl and ethyl; Alk is —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂— or —CH₂C(CH₃)₂CH₂—; X is —CH₂—, —CH(CH₃)— or —C(CH₃)₂—; andQ is phenyl, optionally substituted by one or two substituents selectedfrom C₁-C₃ alkyl, fluoro-(C₁-C₃)alkyl, C₁-C₃ alkoxy, fluoro-(C₁-C₃)alkoxy, halo, and cyano. In this preferred subclass, R₁₁ and R₁₂together with the nitrogen atom to which they are attached may form apiperidine, morpholine, or piperazine ring, optionally substituted byC₁-C₃ alkyl or fluoro. Furthermore, in this preferred subclass Q may beunsubstituted phenyl.

Specific compounds of the invention include those of the Examplesherein, and their pharmaceutically acceptable salts.

Utility

The present invention may be employed in respect of a human or animalsubject, more preferably a mammal, more preferably a human subject.

As used herein, the term “treatment” as used herein includesprophylactic treatment.

Compounds of the invention may be used alone in the treatment of cancersand autoimmune disorders such as organ transplant rejection, lupus,multiple sclerosis, rheumatoid arthritis and osteoarthritis. However, asexplained above in the background to the present invention, the mainutility of inhibitors of CHK1 is considered to be their ability toimprove the efficacy of current DNA-damage inducing radiotherapy orchemotherapeutic regimens for cancer treatment. The compound of formula(I) is therefore preferably used in combination for the treatment ofcancer with radiation therapy or one or more cytotoxic or cytostaticdrugs, or drugs which induce cytotoxicity or cytostasis. The compound ofthe invention and the other component may be in the same pharmaceuticalformulation or in separate formulations for administrationsimultaneously or sequentially.

Non-limiting examples of chemotherapeutic agents, radiotheraputic agentsand other active and ancillary agents are set forth below.

(i) Alkylating agents.

(ii) Nitrogen mustards such as

chlorambucil cyclophosphamide ifosfamide mechlorethamine melphalan(iii) Nitrosoureas such as

carmustine (BCNU) lomustine (CCNU) semustine (methyl-CCNU)(iv) Ethylenimine/Methyl-melamine such as

hexamethylmelamine (HMM/altetamine) thriethylenemelamine (TEM)trethylene thiophosphoramide (thiotepa)(v) Alkyl sulphonates such as busulphan.(vi) Triazines such as dacarbazine (DTIC).(vii) Antimetabolites such as the Folic acid analogues such as

Methoxtrexate pemetrexed (multi-targeted antifolate) Trimetrexate(viii) Pyrimidine analogues such as

2,2′-difluorodeoxy-cytidine 5-azacytidine 5-fluorouracil cytosinearabinoside (araC/cytarabine) Fluorodeoxyuridine Gemcitabine(ix) Purine analogues such as

2-chlorodeoxyadenosine (cladribine/2-CdA) 2′-deoxycoformycin(pentostatin) 6-Mercaptopurine 6-thioguanine Azathioprineerthyrohydroxynonyl-adenine (EHNA) fludarabine phosphate(x) Type I Topoisomerase Inhibitors such as

camptothecin irinotecan topotecan(xi) Biological response modifiers such as G-CSF and GM-CSF.(xii) Differentiation agents such as retinoic acid derivatives.(xiii) Hormones and antagonists.(xiv) Adrenocorticosteroids/antagonists such as

ainoglutethimide dexamethasone prednisone and equivalents(xv) Progestins such as

hydroxyprogesterone caproate medroxyprogesterone acetate megestrolacetate(xvi) Estrogens such as

diethylstilbestrol ethynyl estradiol/equivalents(xvii) Antiestrogens such as tamoxifen.(xviii) Andogens such as

testosterone propionate fluoxymesterone/equivalents(xix) Anti-androgens such as

Flutimide gonadotropin-releasing hormone analogues Leuprolide(xx) Nonsteroidal antiandrogens.(xxi) Natural products.(xxii) Antimitotic drugs.(xxiii) Taxanes such as

docetaxel (Taxotere) estramustine/estramustine phosphate Paclitaxelvinblastine (VLB) vinca alkaloids Vincristine Vinorelbine(xxiv) Epipodophylotoxins such as etoposide or teniposide.(xxv) Antibiotics such as

actimomycin D aphidicolin Bleomycin Dactinomycin daunomycin(rubidomycin) doxorubicin (adriamycin) mitomycin CMitroxantroneidarubicin splicamycin (mithramycin)(xxvi) Enzymes such as L-asparaginase and L-arginase.(xxvii) Radiosensitizers such as

5-bromodeozyuridine 5-idoddeoxyuridine BromodeoxycytidineDesmethylmisonidazole EO9 Etanidazole Metronidazole MisonidazoleNicotinamide Nimorazole Pimonidazole RB 6145 RSU 1069 SR4233(xxviii) Platinum coordination complexes such as

Anthracenedione Carboplatin Cisplatin Mitoxantrone oxaliplatin(xxix) Substituted ureas such as hydroxyurea.(xxx) Methyhydrazine derivatives such as N-methylhyrazine (MIH) andprocarbazine.(xxxi) Adrenocortical suppressant mitocane (o,p′-DDD) ainoglutethimide.(xxxii) Cytokines such as interferon (α, β, γ) and interleukin-2.(xxxiii) Photosensitisers such as

bacteriochlorophyll-a benzoporphyrin derivatives hematoporphyrinderivatives napthalocyanines Npe6 pheboride-a photofrin phthalocyaninestin etioporphyrin (SnET2) zinc phthalocyanines(xxxiv) Radiation such as

gamma radiation infrared radiation microwave radiation ultraviolet lightvisible light X-ray

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination and the causative mechanism and severity ofthe particular disease undergoing therapy. In general, a suitable dosefor orally administrable formulations will usually be in the range of0.1 to 3000 mg, once, twice or three times per day, or the equivalentdaily amount administered by infusion or other routes. However, optimumdose levels and frequency of dosing will be determined by clinicaltrials as is conventional in the art.

The compounds with which the invention is concerned may be prepared foradministration by any route consistent with their pharmacokineticproperties. The orally administrable compositions may be in the form oftablets, capsules, powders, granules, lozenges, liquid or gelpreparations, such as oral, topical, or sterile parenteral solutions orsuspensions. Tablets and capsules for oral administration may be in unitdose presentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone, fillers for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine, tablettinglubricant, for example magnesium stearate, talc, polyethylene glycol orsilica, disintegrants for example potato starch, or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, glucose syrup, gelatin hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia, non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol, preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

For topical application to the skin, the drug may be made up into acream, lotion or ointment. Cream or ointment formulations which may beused for the drug are conventional formulations well known in the art,for example as described in standard textbooks of pharmaceutics such asthe British Pharmacopoeia.

The active ingredient may also be administered parenterally in a sterilemedium. Depending on the vehicle and concentration used, the drug caneither be suspended or dissolved in the vehicle. Advantageously,adjuvants such as a local anaesthetic, preservative and buffering agentscan be dissolved in the vehicle.

There are multiple synthetic strategies for the synthesis of thecompounds (I) with which the present invention is concerned, but allrely on known chemistry, known to the synthetic organic chemist. Thus,compounds according to formula (I) can be synthesised according toprocedures described in the standard literature and are well-known tothe one skilled in the art. Typical literature sources are “Advancedorganic chemistry”, 4^(th) Edition (Wiley), J March, “ComprehensiveOrganic Transformation”, 2^(nd) Edition (Wiley), R. C. Larock, “Handbookof Heterocyclic Chemistry”, 2^(nd) Edition (Pergamon), A. R. Katritzky),review articles such as found in “Synthesis”, “Acc. Chem. Res.”, “Chem.Rev”, or primary literature sources identified by standard literaturesearches online or from secondary sources such as “Chemical Abstracts”or “Beilstein”. Such literature methods include those of the preparativeExamples herein, and methods analogous thereto.

Examples of methods known in the art of organic chemistry in general, bywhich the compounds of the present invention may be prepared, areincluded in the following reaction schemes and procedures.

EXAMPLES

The following examples illustrate the preparation of specific compoundsof the invention and are not intended to be limiting of the full scopeof the invention.

Example 1 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid(1-benzyl-1H-pyrazol-4-yl)-amide

The title compound was prepared according to the route outlined inScheme 1.

Step 1: Preparation of 5-Iodo-6-(2-trimethylsilanyl-ethoxy)-nicotinicacid methyl ester (1a)

6-Hydroxy-5-iodo-nicotinic acid methyl ester (2.0 g, 7.17 mmol) wasstirred in anhydrous 1,2-dimethoxyethane (60 mL) at ambient temperature,with potassium fluoride (4.17 g, 71.7 mmol).2-(Trimethylsilyl)ethoxymethyl chloride (1.20 g, 1.27 mL, 7.17 mmol) wasadded drop wise and the reaction stirred at ambient temperature for 3hours. The reaction mixture was filtered through celite, and the filtercake washed with methanol (2×25 mL). The filtrate and the washings werecombined and concentrated in vacuo. The residue was partitioned betweenwater and dichloromethane, and the organic layer was separated. Theaqueous was extracted with a further portion of dichloromethane and thecombined dichloromethane layers were dried (Na₂SO₄) and concentrated invacuo. The resultant crude product was purified by flash chromatographyon SiO₂ eluting first with 20% ethyl acetate/hexane and then 66% ethylacetate/hexane to firstly afford the undesired oxygen substitutedcompound and then the desired title compound as an off-white solid, 2.28g, 78%.

Step 2: Preparation of2-[5-Methoxycarbonyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (1 b)

Intermediate (1a), 5-iodo-6-(2-trimethylsilanyl-ethoxy)-nicotinic acidmethyl ester (1.14 g, 2.79 mmol), 1-(tert-butoxycarbonyl)indole-2-boronic acid (1.09 g, 4.18 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.1 g, 0.143 mmol), potassium acetate (0.82 g,8.37 mmol) and anhydrous N,N-dimethylformamide (15 mL) were combined ina 20 mL microwave vial. The contents of the vial were degassed and thenwere heated at 60° C. for 20 minutes under microwave irradiation. Thereaction mixture was concentrated in vacuo. The residue was partitionedbetween water and dichloromethane, and the organic layer was separated.The aqueous was extracted with a further portion of dichloromethane andthe combined dichloromethane layers were dried (Na₂SO₄) and concentratedin vacuo. The resultant crude product was purified by flashchromatography on SiO₂ eluting with 20% ethyl acetate/hexane to affordthe desired title compound as an oil 1.39 g, 100%.

Step 3: Preparation of2-[5-Carboxy-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (1c)

Intermediate (1 b),2-[5-methoxycarbonyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (2.88 g, 5.78 mmol) was stirred in a mixture oftetrahydrofuran (40 mL) and water (20 mL). Lithium hydroxide (0.469 g,11.2 mmol) was added and the reaction stirred at reflux for 2 hours.After cooling the reaction mixture was concentrated in vacuo, and theresidue was taken up in water and the pH adjusted to 5 with the carefuladdition of an aqueous 2M hydrochloric acid solution. This aqueoussolution was extracted with dichloromethane (×3), and the combinedextracts were washed with brine, dried (Na₂SO₄) and concentrated invacuo to afford the desired title compound as a yellow solid 2.30 g,85%.

Step 4: Preparation of2-[5-(1-Benzyl-1H-pyrazol-4-ylcarbamoyl)-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (1d)

Intermediate (1c),2-[5-carboxy-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (300 mg, 0.62 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (357 mg,1.86 mmol), 1-hydroxybenzotriazole hydrate (251 mg, 1.86 mmol),N,N-diisopropylethylamine (320 mg, 0.431 mL, 2.48 mmol),1-benzyl-1H-pyrazol-4-ylamine (322 mg, 1.86 mmol) and tetrahydrofuran(12 mL) were combined in a 20 mL microwave vial. The contents of thevial were heated at 90° C. for 30 minutes under microwave irradiation.The reaction mixture was concentrated in vacuo. The residue waspartitioned between water and dichloromethane, and the organic layer wasseparated. The aqueous was extracted with a further portion ofdichloromethane and the combined dichloromethane layers were dried(Na₂SO₄) and concentrated in vacuo. The resultant crude product waspurified by flash chromatography on SiO₂ eluting with 20% ethylacetate/hexane and then 2% methanol/dichloromethane to afford thedesired title compound as a solid, 315 mg, 80%.

Step 5: Preparation of Title compound:5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid(1-benzyl-1H-pyrazol-4-yl)-amide

Intermediate (1d),2-[5-(1-benzyl-1H-pyrazol-4-ylcarbamoyl)-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (315 mg, 0.492 mmol) was stirred intetrahydrofuran (15 mL) and 1,2-diaminoethane (89 mg, 98 ul, 1.48 mmol)was added followed by tetrabutylammonium fluoride solution 1.0M intetrahydrofuran (2.46 mL, 2.46 mmol). The reaction mixture was heated atreflux for 18 hours, and cooled to ambient temperature. The reactionmixture was concentrated in vacuo. The residue was partitioned betweenwater and dichloromethane, and the organic layer was separated. Theaqueous was extracted with a further portion of dichloromethane and thecombined dichloromethane layers were washed with water (×3) dried(Na₂SO₄) and concentrated in vacuo. The resultant crude product waspurified by flash chromatography on SiO₂ eluting with dichloromethane—8%methanol/dichloromethane (gradient) to afford a solid. This solid wastriturated with diethyl ether to afford the desired title compound as ayellow solid, 41 mg, 20%.

LC/MS: RT=2.33 Min (270 nm), m/z=410, 411 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 5.33 (s, 2H), 6.97-7.01 (m, 1H), 7.07-7.11 (m, 1H),7.24-7.38 (m, 6H), 7.49 (d, 1H), 7.55 (d, 1H), 7.61 (s, 1H), 8.10 (s,1H), 8.11 (d, 1H), 8.56 (d, 1H), 10.30 (s, 1H), 11.50 (s, 1H), 12.30 (s,1H).

Example 2 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid[1-(4-methoxy-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared according to the route outlined inScheme 1.

Step 1: Preparation of 4-Nitro-1H-pyrazole (1e)

Pyrazole (16 g, 235 mmol) was added in portions to sulfuric acid, 98%,(100 mL) keeping the temperature below 40° C. To this solution was addednitric acid, 70%, (16 mL) maintaining the temperature below 55° C. Afteraddition the reaction was heated at 55° C. for 3 hours, and then cooledto 0° C., before carefully adding to ice/water (400 mL) with stirring.This mixture was neutralized by the careful addition of aqueous 50%sodium hydroxide solution using external cooling and efficient stirring.The resultant solution was extracted with ethyl acetate (3×300 mL), andthe combined extracts were washed with brine (2×250 mL) dried (Na₂SO₄)and concentrated in vacuo to yield a white solid, which was used withoutfurther purification, 24.74 g, 93%.

Step 2: Preparation of 1-(4-Methoxy-benzyl)-4-nitro-1H-pyrazole

4-Nitro-1H-pyrazole (565 mg, 5 mmol) was stirred in acetonitrile (15 mL)with potassium carbonate (829 mg, 6 mmol) for 5 minutes and then4-methoxybenzyl chloride (861 mg, 0.746 mL, 5.5 mmol) was added. Thereaction was stirred at ambient temperature for 18 hours, and thenpartitioned between ethyl acetate and an aqueous 2M hydrochloric acidsolution. The organic layer was separated and the aqueous was extractedwith a further portion of ethyl acetate. The combined ethyl acetatelayers were dried (Na₂SO₄) and concentrated in vacuo. The resultantcrude product was purified by flash chromatography on SiO₂ eluting with20% ethyl acetate/hexane and then 50% ethyl acetate/dichloromethane toafford the desired title compound as an oil, 1.08 g, 93%.

Step 3: Preparation of 1-(4-Methoxy-benzyl)-1H-pyrazol-4-ylamine

1-(4-Methoxy-benzyl)-4-nitro-1H-pyrazole (240 mg, 1.03 mmol) was stirredin ethanol (10 mL) and the flask was evacuated and then flushed withnitrogen. Platinum, sulfided, 5 wt. % on carbon, reduced, dry (10 mg,catalytic amount) was added and after two vacuum/H₂ cycles to replacethe nitrogen inside with hydrogen, the mixture was shaken for 18 hoursunder ordinary hydrogen pressure (1 atm). The reaction mixture wasfiltered and the filtrate was concentrated in vacuo to yield a red oil,which was used without further purification, 168 mg, 81%.

Step 4: Preparation of2-[5-[1-(4-Methoxy-benzyl)-1H-pyrazol-4-ylcarbamoyl]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester

The title compound was prepared according to the experimental used inExample 1, Step 4 using intermediate (1c) and1-(4-methoxy-benzyl)-1H-pyrazol-4-ylamine. After the usual aqueous workup, the resultant crude product was purified by flash chromatography onSiO₂ eluting with hexane—50% ethyl acetate/hexane. This afforded thetitle compound as a pink solid, 180 mg, 50%.

Step 5: Preparation of Title Compound:5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid[1-(4-methoxy-benzyl)-1H-pyrazol-4-yl]amide

The title compound was prepared according to the experimental used inExample 1, Step 5 with2-[5-[1-(4-methoxy-benzyl)-1H-pyrazol-4-ylcarbamoyl]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester.

After the usual aqueous work up the resultant crude product was purifiedby flash chromatography on SiO₂ eluting with 50% ethylacetate/dichloromethane and then 5% methanol/dichloromethane to afford asolid which was further purified via preparative HPLC at pH9, to furnishthe title compound as a yellow solid, 40 mg, 36%.

LC/MS: RT=2.29 Min (270 nm), m/z=440 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 3.75 (s, 3H), 5.25 (s, 2H), 6.91-6.95 (m, 2H),6.98-7.03 (m, 1H), 7.09-7.13 (m, 1H), 7.23-7.28 (m, 3H), 7.51 (d, 1H),7.56 (d, 1H), 7.6 (d, 1H), 8.06 (s, 1H), 8.12 (d, 1H), 8.57 (d, 1H),10.3 (s, 1H), 11.51 (br s, 1H), 12.5 (br s, 1H).

Example 3 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid[1-(2-methyl-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared according to the route outlined inScheme 2.

Step 1: Preparation of 1H-Pyrazol-4-ylamine (2f)

Intermediate (1e), 4-nitro-1H-pyrazole (2.8 g, 24.8 mmol), was stirredin ethanol (200 mL) and the flask was evacuated and then flushed withnitrogen. Palladium, 10 wt. % on activated carbon (300 mg, catalyticamount) was added and after two vacuum/H₂ cycles to replace the nitrogeninside with hydrogen, the mixture was shaken for 18 hours under ordinaryhydrogen pressure (1 atm). Palladium, 10 wt. % on activated carbon (300mg) was added and after two vacuum/H₂ cycles to replace the nitrogeninside with hydrogen, the mixture was shaken for a further 4 hours. Thereaction mixture was filtered through celite and the filter cake waswashed through with ethanol (2×50 mL). The combined washings and thefiltrate were concentrated in vacuo. The residue obtained was trituratedwith ethyl acetate to yield a light pink solid, 1.48 g, 72%. Thefiltrate subsequently obtained was concentrated in vacuo to yieldanother batch of sufficiently pure material, 0.54 g, 26%, as a dark pinksolid.

Step 2: Preparation of2-[2-oxo-5-(1H-pyrazol-4-ylcarbamoyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (2d)

To a solution of intermediate (1c),2-[5-carboxy-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester, (3 g, 6.2 mmol) in tetrahydrofuran (100 mL) wasadded intermediate (2f), 1H-pyrazol-4-ylamine (0.62 g, 7.46 mmol),1-hydroxybenzotriazole hydrate (1.09 g, 8.07 mmol),N,N-diisopropylethylamine (2.4 g, 3.24 mL, 18.6 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.55 g,8.07 mmol). The reaction mixture was heated at 40° C. for 2 hours. Thereaction mixture was cooled and partitioned between ethyl acetate andaqueous saturated sodium hydrogen bicarbonate solution. The ethylacetate layer was separated and washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. The resultant crude product was purified by flashchromatography on SiO₂ eluting with hexane—66% ethyl acetate/hexane(gradient) to afford the desired title compound as a yellow solid, 1.36g, 40%.

Step 3:2-[5-[1-(2-Methyl-benzyl)-1H-pyrazol-4-ylcarbamoyl]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (2e)

Intermediate (2d),2-[2-oxo-5-(1H-pyrazol-4-ylcarbamoyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (50 mg, 0.091 mmol), Cs₂CO₃ (45 mg, 0.136 mmol)and 2-methylbenzyl bromide (21 mg, 15 ul, 0.11 mmol) were stirred inN,N-dimethylformamide (5 mL) at ambient temperature for 48 hours. Theinorganics were separated via filtration and the filtrate wasconcentrated in vacuo. The resultant crude product was purified by flashchromatography on SiO₂ eluting with hexane—50% ethyl acetate/hexane(gradient) to afford the desired title compound as a solid, 55 mg, 93%.

Step 4: Preparation of Title Compound:5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid[1-(2-methyl-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared according to the experimental used inExample 1, Step 5 with intermediate (2e),2-[5-[1-(2-methyl-benzyl)-1H-pyrazol-4-ylcarbamoyl]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester. After the usual aqueous work up, the resultantcrude product was purified by trituration with acetonitrile. Thisafforded the title compound as a yellow solid, 30 mg, 84%.

LC/MS: RT=2.41 Min (270 nm), m/z=424 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.29 (s, 3H), 5.33 (s, 2H), 6.98 (br t, 2H), 7.08(br t, 1H), 7.17 (m, 4H), 7.29 (s, 1H), 7.47 (d, 1H), 7.54 (d, 1H), 7.69(br s, 1H), 8.00 (s, 1H), 8.12 (br s, 1H), 8.74 (br m, 1H), 10.50 (br s,1H), 11.57 (br s, 1H)

Example 4 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid[1-(3-methyl-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 2,following the same procedures as for Example 3.

LC/MS: RT=2.41 Min (270 nm), m/z=424 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₄ MeOD): δ 2.30 (s, 3H), 5.28 (s, 2H), 7.05 (m, 5H), 7.15 (s,1H), 7.22 (t, 1H), 7.42 (d, 1H), 7.54 (t, 1H), 7.68 (s, 1H), 8.07 (m,2H), 8.61 (d, 1H), NHs not seen.

Example 5 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid[1-(4-methyl-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 2,following the same procedures as for Example 3.

LC/MS: RT=2.31 Min (270 nm), m/z=424 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 3.31 (s, 3H), 5.26 (s, 2H), 6.98 (td, 1H), 7.09 (td,1H), 7.15 (br s, 4H), 7.24 (d, 1H), 7.48 (dd, 1H), 7.54 (d, 1H), 7.58(d, 1H), 8.05 (s, 1H), 8.01 (br s, 1H), 8.55 (d, 1H) 10.27 (s, 1H),11.49 (br s, 1H), 12.46 (br s, 1H)

Example 6 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid[1-(3-cyano-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 2,following the same procedures as for Example 3.

LC/MS: RT=2.12 Min (270 nm), m/z=435 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 5.41 (s, 2H), 6.98 (t, 1H), 7.08 (t, 1H), 7.24 (s,1H), 7.49 (d, 1H), 7.55 (m, 3H), 7.63 (s, 1H), 7.69 (s, 1H), 7.78 (dt,1H.), 8.11 (d, 1H), 8.19 (s, 1H), 8.55 (d, 1H), 10.35 (s, 1H), 11.52 (s,1H), 12.42 (br s, 1H)

Example 7 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid[1-(4-cyano-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 2,following the same procedures as for Example 3.

LC/MS: RT=2.15 Min (270 nm), m/z=435 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 5.41 (s, 2H), 6.99 (t, 1H), 7.09 (t, 1H), 7.25 (s,1H), 7.36 (d, 2H), 7.49 (d, 1H), 7.54 (d, 1H), 7.64 (s, 1H), 7.83 (d,2H), 8.12 (br m, 1H), 8.19 (s, 1H), 8.55 (d, 1H), 10.33 (s, 1H), 11.50(s, 1H), 12.47 (br s, 1H)

Example 8 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid[1-(2-fluoro-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 2,following the same procedures as for Example 3.

LC/MS: RT=2.24 Min (270 nm), m/z=428 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 5.39 (s, 2H), 6.98 (td, 1H), 7.11 (td, 1H), 7.21 (m,4H), 7.37 (m, 1H), 7.48 (d, 1H), 7.54 (d, 1H), 7.61 (d, 1H), 8.11 (m,2H), 8.55 (d, 1H), 10.30 (s, 1H), 11.49 (br s, 1H), 12.47 (br s, 1H)

Example 9 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid[1-(3-fluoro-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 2,following the same procedures as for Example 3.

LC/MS: RT=2.24 Min (270 nm), m/z=428 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 5.35 (s, 2H), 6.98 (t, 1H), 7.04 (m, 5H), 7.24 (brs, 1H), 7.40 (qd, 1H), 7.48 (d, 1H), 7.54 (d, 1H), 7.62 (s, 1H), 8.11(d, 1H), 8.14 (s, 1H), 8.55 (d, 1H), 10.30 (br s, 1H), 11.53 (br s, 1H)

Example 10 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid [1-(4-fluoro-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by simple modifications of the protocoldescribed for Example 3, but still using the route outlined in Scheme 2.

The principal modification was for Step 3, and this is described below.

2-[2-oxo-5-(1H-pyrazol-4-ylcarbamoyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester, (2d), (100 mg, 0.182 mmol) was stirred in acetone(5 mL) with potassium carbonate (126 mg, 0.91 mmol) and 4-fluorobenzylbromide (41 mg, 27 ul, 0.218 mmol) was added. The reaction mixture washeated at 50° C. for 8 hours, and then cooled to ambient temperature.The inorganics were separated via filtration, and the filter cake waswashed through with ethyl acetate (2×5 mL). The combined washings andthe filtrate were concentrated in vacuo, and the residue obtained waspurified by flash chromatography on SiO₂ eluting with 20% ethylacetate/hexane to afford the desired compound as an oil, 87 mg, 72%.

The title compound was isolated as a yellow solid.

LC/MS: RT=2.29 Min (270 nm), m/z=428 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 5.35 (s, 2H), 6.98-7.03 (m, 1H), 7.09-7.14 (m, 1H),7.18-7.24 (m, 2H), 7.27 (d, 1H), 7.31-7.36 (m, 2H), 7.51 (d, 1H), 7.57(d, 1H), 7.63 (d, 1H), 8.12-8.15 (m, 2H), 8.58 (d, 1H), 10.34 (s, 1H),11.54 (br s, 1H), 12.1 (br s, 1H).

Example 11 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid [1-(3,4-difluoro-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 2,following the same procedures as for Example 10.

LC/MS: RT=1.21 Min (270 nm), m/z=446 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 5.35 (s, 2H), 7.00 (t, 1H), 7.10 (t, 1H), 7.30 (brs, 1H), 7.35 (m, 1H), 7.45 (q, 1H), 7.55 (d, 1H), 7.60 (d, 1H), 7.70 (s,1H) 8.15 (d, 1H), 8.20 (s, 1H), 8.60 (d, 1H), 10.35 (s, 1H), NH (×3) notseen.

Example 12 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid [1-(4-chloro-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 2,following the same procedures as for Example 10.

LC/MS: RT=1.24 Min (270 nm), m/z=444 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 5.40 (d, 2H), 7.05 (t, 1H), 7.15 (t, 1H), 7.35 (d,2H), 7.50 (d, 2H), 7.55 (d, 1H), 7.65 (d, 1H), 7.70 (s, 1H) 8.20 (d,1H), 8.25 (s, 1H), 8.65 (d, 1H), 10.45 (s, 1H), NH (×3) not seen.

Example 13 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid [1-(3,5-difluoro-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 2,following the same procedures as for Example 10.

LC/MS: RT=1.22 Min (270 nm), m/z=446 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 5.40 (s, 2H), 7.00 (m, 2H), 7.05 (t, 1H), 7.15 (t,1H), 7.25 (m, 1H), 7.30 (d, 1H), 7.55 (d, 1H), 7.60 (d, 1H), 7.70 (s,1H) 8.15 (d, 1H), 8.25 (s, 1H), 8.60 (d, 1H), 10.40 (s, 1H), NH (×2) notseen.

Example 14 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid [1-(3-fluoro-4-methyl-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 2,following the same procedures as for Example 10.

LC/MS: RT=1.25 Min (270 nm), m/z=442 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 2.25 (s, 3H), 5.30 (s, 2H), 7.00 (m, 3H), 7.10 (t,1H), 7.30 (m, 2H), 7.50 (d, 1H), 7.60 (d, 1H), 7.70 (s, 1H) 8.15 (m,2H), 8.55 (d, 1H), 10.35 (s, 1H), NHs not seen.

Example 155-[5-(4-Methyl-piperazine-1-carbonyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid (1-benzyl-1H-pyrazol-4-yl)-amide

The title compound was prepared by the route outlined in Scheme 3.

Step 1: Preparation of 1H-Indole-5-carboxylic acid benzyl ester (3a)

To a solution of indole-5-carboxylic acid (2.63 g, 16.34 mmol) inN,N-dimethylformamide (50 mL) was added sodium bicarbonate (8.24 g,98.04 mmol) and benzyl bromide (11.66 mL, 98.04 mmol). The reaction wasstirred for 48 hours at ambient temperature under nitrogen. The reactionwas then partitioned between ethyl acetate and water. The organic layerwas separated and the aqueous extracted with a further portion of ethylacetate. The combined organic layers were dried (MgSO₄) and evaporatedin vacuo. The resultant crude product was purified by flashchromatography on SiO₂, eluting with 20% ethyl acetate/hexane followedby 50% ethyl acetate/hexane to afford the title compound as an oil, 4.82g, quantitative.

Step 2: Preparation of Indole-1,5-dicarboxylic acid 5-benzyl ester1-tert-butyl ester (3b)

To a solution of intermediate (3a), 1H-indole-5-carboxylic acid benzylester, (4.8 g, 16.34 mmol) in acetonitrile (100 mL) was addeddi-tert-butyl dicarbonate (3.92 g, 17.97 mmol) and4-dimethylaminopyridine (0.2 g, 1.63 mmol). The reaction was stirred atambient temperature under nitrogen for 12 hours. The reaction wasconcentrated in vacuo and the resultant crude product was purified byflash chromatography on SiO₂, eluting with 20% ethyl acetate/hexane toafford the title compound as an off white solid, 5.04 g, 88%.

Step 3: Preparation of Indole-2-boronic acid-1,5-dicarboxylic acid5-benzyl ester 1-tert-butyl ester (3c)

To a solution of intermediate (3b), indole-1,5-dicarboxylic acid5-benzyl ester 1-tert-butyl ester, (5.04 g, 14.36 mmol) intetrahydrofuran (50 mL) at 0° C. was added triisopropyl borate (5 mL,21.54 mmol). Freshly prepared lithium diisopropylamide solution (18.67mmol) in tetrahydrofuran (10 mL) was then added drop wise at 0° C. andthe reaction was stirred at 0° C. for 2 hours under nitrogen. The pH ofthe reaction mixture was adjusted to pH7 by the careful addition of anaqueous 2M hydrochloric acid solution and stirred at ambient temperaturefor a further 30 minutes. The organics were separated, dried (Na₂SO₄)and concentrated in vacuo. This afforded the title compound, which wasused without further purification, 5.05 g, quantitative.

Step 4: Preparation of2-[5-Methoxycarbonyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1,5-dicarboxylicacid 5-benzyl ester 1-tert-butyl ester (3d)

To a solution of intermediate (1a),5-iodo-6-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,6-dihydro-pyridine-3-carboxylicacid ester, (2.94 g, 7.18 mmol) in N,N-dimethylformamide (16 mL) wasadded intermediate (3c), indole-2-boronic acid-1,5-dicarboxylic acid5-benzyl ester 1-tert-butyl ester, (5.05 g, 14.36 mmol) and potassiumacetate (2.11 g, 21.54 mmol). The reaction mixture was degassed for 10minutes after which bis(triphenylphosphine)palladium(II) dichloride(0.25 g, 0.359 mmol) was added and the reaction mixture degassed for afurther 10 minutes. The reaction mixture was then heated to 60° C. inthe microwave for 20 mins. The reaction mixture was concentrated invacuo, and the residue partitioned between dichloromethane and water.The organic layer was separated and the aqueous extracted with a furtherportion of dichloromethane. The combined organics were dried (MgSO₄) andevaporated in vacuo. The resultant crude product was purified by flashchromatography on SiO₂, eluting with 20% ethyl acetate/hexane to affordthe title compound as a yellow oil, 2.07 g, 46%.

Step 5: Preparation of2-[5-Methoxycarbonyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1,5-dicarboxylicacid 1-tert-butyl ester (3e)

To a degassed solution of intermediate (3d),2-[5-methoxycarbonyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1,5-dicarboxylicacid 5-benzyl ester 1-tert-butyl ester, (2.07 g, 3.27 mmol) in methanol(30 mL) was added palladium, 10 wt. % on activated carbon (50 mg) andthe reaction further degassed. The reaction was heated to 30° C. for 72hours under a hydrogen atmosphere. The reaction mixture was thenfiltered through a celite pad and the pad rinsed with hot methanol (20mL). The combined filtrate and washings were concentrated in vacuo andpoured onto 4×10 g PE-AX columns. The columns were then flushed withmethanol and eluted with 20% acetic acid/methanol. The combined organicswere concentrated in vacuo. To the residue was added ether and this wasconcentrated in vacuo. This process was repeated twice more andfurnished the desired title compound as a brown solid, 627 mg, 35%.

Step 6: Preparation of2-[5-Methoxycarbonyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-methyl-piperazine-1-carbonyl)-indole-1-carboxylicacid tert-butyl ester (3f)

The title compound was prepared according to the experimental used inExample 3, Step 2 with intermediate (3e),2-[5-methoxycarbonyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1,5-dicarboxylicacid 1-tert-butyl ester. After the usual aqueous work up, the crudeproduct was purified by flash chromatography on SiO₂, eluting with 6%methanol/dichloromethane to afford the title compound as a yellow gum,219 mg, 95%.

Step 7: Preparation of2-[5-Carboxy-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-methyl-piperazine-1-carbonyl)-indole-1-carboxylicacid tert-butyl ester (3g)

The title compound was prepared according to the experimental used inExample 1, Step 3 with intermediate (3f),2-[5-methoxycarbonyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-methyl-piperazine-1-carbonyl)-indole-1-carboxylicacid tert-butyl ester. After the usual work up, the desired titlecompound was isolated as a yellow solid, 142 mg, 66%.

Step 8: Preparation of2-[5-(1-Benzyl-1H-pyrazol-4-ylcarbamoyl)-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-methylpiperazine-1-carbonyl)-indole-1-carboxylicacid tert-butyl ester (3h)

The title compound was prepared according to the experimental used inExample 1, Step 4 with intermediate (3g),2-[5-carboxy-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-methyl-piperazine-1-carbonyl)-indole-1-carboxylicacid tert-butyl ester. After the usual work up, the crude product waspurified by flash chromatography on SiO₂, eluting with 5%methanol/dichloromethane to afford the title compound as a brown foam,178 mg, quantitative.

Step 9: Preparation of title compound5-[5-(4-Methyl-piperazine-1-carbonyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid (1-benzyl-1H-pyrazol-4-yl)-amide

The title compound was prepared according to the experimental used inExample 1, Step 5 with intermediate (3h),2-[5-(1-benzyl-1H-pyrazol-4-ylcarbamoyl)-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-methylpiperazine-1-carbonyl)-indole-1-carboxylicacid tert-butyl ester. After the usual work up the crude product wastaken up in methanol (1 mL) and loaded onto a 5 g SCX column. The columnwas flushed with methanol and then eluted with ammonia solution 7N inmethanol. The eluent was concentrated in vacuo and the residue furtherpurified by preparative HPLC at pH 4 to afford the title compound as abrown solid, 13 mg, 10%.

LC/MS RT=1.52 Min (270 nm), m/z=536 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.21 (s, 3H), 2.33 (br m, 4H), 3.53-3.56 (br m, 4H)0.33 (s, 2H), 7.13 (dd, 1H), 7.31 (m, 6H), 7.53 (d, 1H), 7.61 (s, 2H),8.10 (s, 1H), 8.14 (d, 1H), 8.58 (d, 1H), 10.31 (s, 1H), 11.72 (s, 1H),12.5 (s, 1H).

Example 166-oxo-5-(5-piperazin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridine-3-carboxylicacid (1-benzyl-1H-pyrazol-4-yl)-amide

The title compound was prepared by the route outlined in Scheme 4.

Step1: Preparation of Indole-2-boronicacid-5-(4-tert-butoxycarbonyl-piperazin-1-ylmethyl)-indole-1-carboxylicacid tert-butyl ester (4a)

To a stirred solution of indole-5-carboxaldehyde (2 g, 13.8 mmol) intoluene (10 mL) was added 4-dimethylaminopyridine (1 mol %, 10 mg) anddi-tert-butyl dicarbonate (3.14 g, 14.5 mmol) and the mixture stirred atambient temperature for 30 minutes. After this time, tert-butylpiperazine-1-carboxylate (2.56 g, 13.8 mmol) was added followed bysodium triacetoxyborohydride (4.44 g, 20.7 mmol) in portions. Afterstirring for 90 minutes, a 2.5% v/v solution of acetic acid in water (10mL) was added, stirred briefly and the organic layer separated. Thislayer was washed with water (50 mL) and concentrated to near dryness.Methanol (50 mL) was added and the reaction concentrated to dryness. Theresidue was triturated with toluene and the liquors concentrated todryness to yield the protected indole. This residue was dissolved inanhydrous tetrahydrofuran (6 mL).

This solution was added via syringe into a nitrogen-purged flask andcooled to 5° C. Triisopropyl borate (4.77 mL, 20.7 mmol) was added,followed by slow addition of lithium diisopropylamide solution 2M intetrahydrofuran (8.95 mL, 17.9 mmol), ensuring the temperature remainedbetween 0 and 5° C. The mixture was stirred at 5° C. for one hour thenquenched by the addition of an aqueous 2M hydrochloric acid solution (2mL). The pH was adjusted to 7 with aqueous ammonia solution, the icebath removed and the resultant biphasic mixture stirred at ambienttemperature for 30 minutes. The organic layer was separated, dried(MgSO₄) and concentrated in vacuo to afford the title compound, 6.34 g,quantitative.

Step 2: Preparation of5-(4-tert-Butoxycarbonyl-piperazin-1-ylmethyl)-2-[5-methoxycarbonyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (4b)

Intermediate (4a), indole-2-boronicacid-5-(4-tert-butoxycarbonyl-piperazin-1-ylmethyl)-indole-1-carboxylicacid tert-butyl ester (6.34 g, 13.8 mmol), potassium acetate (2.59 g,26.4 mmol) and intermediate (1a),5-iodo-6-(2-trimethylsilanyl-ethoxy)-nicotinic acid methyl ester (3.51g, 8.6 mmol) were dissolved in N,N-dimethylformamide (70 mL). Thereaction was degassed three times using alternating cycles of vacuum anddry nitrogen and then bis(triphenylphosphine)palladium(II) dichloride(0.45 g, 0.64 mmol) was added. The mixture was again degassed thenheated under a nitrogen atmosphere at 60° C. for one hour. The mixturewas cooled, concentrated to dryness and the residue was partitionedbetween water and ethyl acetate. The organic layer was separated and theaqueous was extracted with a further portion of ethyl acetate. Thecombined ethyl acetate layers were dried (Na₂SO₄) and concentrated invacuo. The resultant crude product was purified by flash chromatographyon SiO₂ eluting with hexane—20% ethyl acetate/hexane (gradient) toafford the desired title compound as a copper coloured solid, 2.4 g,40%.

Step 3: Preparation of5-(4-tert-Butoxycarbonyl-piperazin-1-ylmethyl)-2-[5-carboxy-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (4c)

The title compound was prepared according to the experimental used inExample 1, Step 3 with intermediate (4b),5-(4-tert-butoxycarbonyl-piperazin-1-ylmethyl)-2-[5-methoxycarbonyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester. After the usual work up, the title compound wasisolated as a brown foam, 2.35 g, quantitative.

Step 4: Preparation of2-[5-(1-Benzyl-1H-pyrazol-4-ylcarbamoyl)-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-tert-butoxycarbonyl-piperazin-1-ylmethyl)-indole-1-carboxylicacid tert-butyl ester (4d)

Intermediate (4c),5-(4-tert-butoxycarbonyl-piperazin-1-ylmethyl)-2-[5-carboxy-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester, (1 g, 1.46 mmol), benzyl-1H-pyrazole-4-yl amine(0.75 g, 4.39 mmol), 1-hydroxybenzotriazole hydrate (0.59 g, 4.39 mmol)and tetrahydrofuran (15 mL) were placed in a microwave vial. To thissolution was added N,N-diisopropylethylamine (0.58 g, 0.78 mL, 4.49mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(0.84 g, 4.39 mmol), the vial capped and heated in the microwave at 90°C. for 30 minutes. After cooling, the mixture was concentrated in vacuoand the residue partitioned between water and dichloromethane. Theorganic layer was separated and the aqueous was extracted with a furtherportion of dichloromethane. The combined dichloromethane layers weredried (Na₂SO₄) and concentrated in vacuo. The resultant crude productwas purified by flash chromatography on SiO₂ eluting withdichloromethane—15% methanol/dichloromethane (gradient) to afford thedesired title compound as a yellow foam, 1.0 g, 82%.

Step 5: Preparation of Title Compound6-oxo-5-(5-piperazin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridine-3-carboxylicacid (1-benzyl-1H-pyrazol-4-yl)-amide

To a solution of intermediate (4d),2-[5-(1-benzyl-1H-pyrazol-4-ylcarbamoyl)-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-tert-butoxycarbonyl-piperazin-1-ylmethyl)-indole-1-carboxylicacid tert-butyl ester, 120 mg, 0.14 mmol) in methanol (4 mL) was addedhydrochloric acid, 37% (0.75 mL). The mixture was heated at 90° C. for 3hours. The reaction was allowed to attain ambient temperature and the pHadjusted to 7 by the careful addition of ammonia solution 7N inmethanol. The mixture was concentrated in vacuo and the resultant cruderesidue was purified via preparative HPLC at pH9, to furnish the titlecompound as a yellow solid, 1.83 mg, 3%.

LC/MS: RT=1.59 Min (270 nm), m/z=508 [M+H]⁺. Total run time 3.75 min(short pos).

¹H NMR (d₄ MeOD): δ 2.71 (br t, 4H), 3.18 (t, 4H), 3.70 (s, 2H), 5.32(s, 2H), 7.13 (m, 2H), 7.29 (m, 5H), 7.41 (d, 1H), 7.50 (br s, 1H), 7.68(s, 1H), 8.07 (s, 2H), 8.45 (s, 1H), 8.57 (d, 1H), NHs not seen.

Example 175-(1H-Indol-2-yl)-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid(1-benzyl-1H-pyrazol-4-yl)-amide

The title compound was prepared by the route outlined in Scheme 5.

Step 1: Preparation of (E)-4-[1-Amino-eth-(Z)-ylidene]-pent-2-enedioicacid diethyl ester (5a)

Ethyl propiolate (39.2 g, 41 mL, 400 mmol) was added to ethyl3-aminocrotonate (51.75 g, 400 mmol) and the mixture heated at 90° C.for 90 minutes to give a dark red oil. The mixture was allowed to cool,to give the product as a dark orange solid, 87.0 g (96%).

Step 2: Preparation of 2-Methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid ethyl ester (5b)

A solution of intermediate (5a),(E)-4-[1-amino-eth-(Z)-ylidene]-pent-2-enedioic acid diethyl ester (51g, 225 mmol) in N,N-dimethylformamide (250 mL) was heated at 175° C. for24 hours to give a dark brown solution. The resulting solution wasallowed to cool and a pale brown precipitate slowly formed. Theprecipitate was removed by filtration and the solids washed withdichloromethane (75 mL) and hexane (100 mL) to give a pale yellowpowder. The solids were dried in vacuo (60° C.) to give the titlecompound as a pale yellow powder, 14.45 g (36%)

Step 3: Preparation of5-Iodo-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester(5c)

N-Iodosuccinimide (40 g, 180 mmol) was added to a suspension ofintermediate (5b), 2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acidethyl ester (18.1 g, 100 mmol) in acetonitrile (400 mL), under anitrogen atmosphere. The resulting suspension was heated at 95° C. for 5hours to give an initial orange solution. An off-white precipitateslowly formed. The resulting suspension was allowed to cool and waspoured into water (1200 mL) to give an off-white precipitate. Theseparated by filtration and the solids washed with water (500 mL) togive an off-white powder. The solids were dried in vacuo (60° C.) togive the product as an off-white powder, 28.3 g (92%)

Step 4: Preparation of5-Iodo-2-methyl-6-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,6-dihydro-pyridine-3-carboxylicacid ethyl ester (5d)

The title compound was prepared according to the experimental used inExample 1, Step 1 using intermediate (5c),5-iodo-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethylester. After the usual work up, the resultant crude product was purifiedby flash chromatography on SiO₂ eluting with 20% ethyl acetate/hexane,to give the product as a yellow/green oil, 30.5 g (76%)

Step 5: Preparation of2-Methyl-5-(1-methyl-1H-indol-2-yl)-6-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,6-dihydro-pyridine-3-carboxylicacid ethyl ester. (5e)

A microwave vial (20 mL) was charged with intermediate (5d),5-iodo-methyl-6-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,6-dihydro-pyridine-3-carboxylicacid ethyl ester (0.87 g, 1.99 mmol), potassium carbonate (0.825 g, 5.97mmol), 1-(tert-butoxycarbonyl) indole-2-boronic acid (0.624 g, 2.39mmol), [1,1′-Bis(diphenylphosphino)ferrocene)]dichloropalladium(11),complex with dichloromethane (0.082 g, 5 mol %), tetrahydrofuran (14 mL)and water (2.3 mL). The contents of the vial were degassed and thenheated at 60° C. for 1 hour under microwave irradiation. After cooling,the reaction mixture was partitioned between brine (50 mL) and ethylacetate (50 mL). The organic layer was separated, dried (Na₂SO₄) andconcentrated in vacuo. The resultant crude product was purified by flashchromatography on SiO₂ with hexane—15% ethyl acetate/hexane (gradient)to afford the title compound as a yellow foam, 1.02 g, 97%.

Step 6: Preparation of2-Methyl-5-(1-methyl-1H-indol-2-yl)-6-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,6-dihydro-pyridine-3-carboxylicacid (5f)

The title compound was prepared according to the experimental used inExample 1, Step 3 using intermediate (5e),2-methyl-5-(1-methyl-1H-indol-2-yl)-6-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,6-dihydro-pyridine-3-carboxylicacid ethyl ester. After the usual work up, the title compound wasisolated as a yellow solid, 419 mg, 92%.

Step 7: Preparation of2-Methyl-5-(1-methyl-1H-indol-2-yl)-6-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,6-dihydro-pyridine-3-carboxylicacid (1-benzyl-1H-pyrazol-4-yl)-amide (5g)

The title compound was prepared according to the experimental used inExample 16, Step 4 with intermediate (5f),2-methyl-5-(1-methyl-1H-indol-2-yl)-6-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,6-dihydro-pyridine-3-carboxylicacid. After the usual work up, the crude product was purified by flashchromatography on SiO₂ eluting with hexane—33% ethyl acetate/hexane(gradient) to afford the desired title compound as a yellow solid, 110mg, 84%.

Step 8: Preparation of the Title Compound:5-(1H-Indol-2-yl)-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid(1-benzyl-1H-pyrazol-4-yl)-amide

The title compound was prepared according to the experimental used inExample 1, Step 5 with intermediate (5g),2-methyl-5-(1-methyl-1H-indol-2-yl)-6-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,6-dihydro-pyridine-3-carboxylicacid (1-benzyl-1H-pyrazol-4-yl)-amide. Purification of the crude productwas accomplished using trituration with acetonitrile. The title compoundwas isolated as a yellow solid, 14 mg, 20%.

LC/MS: RT=2.29 Min (270 nm), m/z=424 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.46 (s, 3H), 5.32 (s, 2H), 6.97 (t, 1H), 7.07 (t,1H), 7.22-7.38 (m, 6H), 7.47 (d, 1H), 7.52 (d, 1H), 7.57 (s, 1H), 8.10(s, 1H), 8.26 (s, 1H), 10.31 (s, 1H), 11.39 (s, 1H), 12.28 (br s, 1H).

Example 185-(1H-Indol-2-yl)-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid[1-(3-fluoro-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 5,following the same procedures as for Example 17.

LC/MS: RT=2.28 Min (270 nm), m/z=442 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.47 (s, 3H), 5.35 (s, 2H), 6.97-7.16 (m, 5H), 7.21(s, 1H), 7.40 (m, 1H), 7.47 (d, 1H), 7.52 (d, 1H), 7.59 (s, 1H), 8.16(s, 1H), 8.27 (s, 1H), 10.33 (s, 1H), 11.39 (s, 1H), 12.28 (br s, 1H).

Example 195-(1H-Indol-2-yl)-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid[1-(3,4-difluoro-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 5,following the same procedures as for Example 17.

LC/MS: RT=2.32 Min (270 nm), m/z=460 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.47 (s, 3H), 5.32 (s, 2H), 6.98-7.59 (m, 9H), 8.17(s, 1H), 8.26 (s, 1H), 10.33 (s, 1H), 11.39 (s, 1H), 12.28 (br s, 1H).

Example 20 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6.

Step 1: Preparation of3-Iodo-5-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyridin-2-one (6a)

The title compound was prepared according to the experimental used inExample 1, Step 1 using 2-hydroxy-3-iodo-5-nitro pyridine. After theusual work up, the resultant crude product was purified by flashchromatography on SiO₂ eluting first with hexane and then 20% ethylacetate/hexane to firstly afford the undesired oxygen substitutedcompound and then the desired title compound as a yellow oil, 4.36 g,59%.

Step 2: Preparation of2-[5-Nitro-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (6b)

The title compound was prepared according to the experimental used inExample 17, Step 5 using intermediate (6a),3-iodo-5-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyridin-2-one.After the usual work up, the crude product was purified by flashchromatography on SiO₂ eluting with hexane—20% ethyl acetate/hexane(gradient) to afford the desired title compound as an oil 0.523 g, 64%.

Step 3: Preparation of2-[5-Amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (6c)

A round bottom flask was charged with intermediate (6b),2-[5-nitro-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (0.485 g, 1 mmol), tetrahydrofuran (5 mL) andpalladium acetate (11 mg, 5 mol %). The flask was sealed and purged withnitrogen. While purging the flask with nitrogen, a solution of potassiumfluoride (116 mg, 2 mmol) in water (2 mL), which had been thoroughlydegassed, was added via syringe. The nitrogen inlet was removed andreplaced with a balloon of nitrogen. Poly(methylhydrosiloxane) (0.44 mL)was added drop wise and the reaction was stirred at ambient temperaturefor 18 hours. The reaction mixture was diluted with dichloromethane (20mL) and aqueous saturated sodium bicarbonate solution (20 mL). Theorganic layer was separated, filtered through a bed of celite andconcentrated in vacuo. The resultant crude product was purified by flashchromatography on SiO₂ eluting with hexane—50% ethyl acetate/hexane(gradient) to afford the desired title compound as a brown solid 0.308g, 67%.

Step 4: Preparation of2-[5-[(1-Benzyl-1H-pyrazole-4-carbonyl)-amino]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (6d)

To a solution of (6c),2-[5-amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (0.3 g, 0.659 mmol) in acetonitrile (10 mL) wasadded 1-benzyl-1H-pyrazole-4-carboxylic acid (0.111 g, 0.549 mmol) andtriethylamine (0.133 g, 0.184 mL, 1.32 mmol).O-benzotriazole-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.312g, 0.823 mmol) was added last and the reaction mixture was stirred atambient temperature for 18 hours. The reaction mixture was concentratedin vacuo and the residue was partitioned between ethyl acetate (25 mL)and aqueous saturated sodium hydrogen carbonate solution (20 mL). Theorganic layer was separated and the aqueous was extracted with a furtherportion of ethyl acetate (25 mL). The combined ethyl acetate layers werewashed with brine, dried (Na₂SO₄) and concentrated in vacuo. Theresultant crude product was purified by flash chromatography on SiO₂eluting with hexane—35% ethyl acetate/hexane—50% ethyl acetate/hexane(gradient) to afford the desired title compound as a light brown solid,0.246 g, 70%.

Step 5: Preparation of the Title Compound:1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared according to the experimental used inExample 1, Step 5 with intermediate (6d),2-[5-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester.

The resultant crude product was purified by trituration withacetonitrile, to afford the title compound as a yellow solid, 64 mg,42%.

LC/MS: RT=2.16 Min (270 nm), m/z=410 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 5.41 (s, 2H), 6.99 (t, 1H), 7.06-7.10 (m, 2H),7.29-7.41 (m, 5H), 7.52 (t, 2H), 7.81 (d, 1H), 8.03 (s, 1H), 8.18 (d,1H), 8.40 (s, 1H), 9.77 (s, 1H), 11.54 (s, 1H), 11.98 (br s, 1H).

Example 21 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6,following the same procedures as for Example 20, but using intermediate(6e) in Step 4.

Preparation of 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid (6e)

1H-Pyrazole-4-carboxylic acid ethyl ester (1 g, 7.14 mmol) was stirredin acetone (15 mL) with potassium carbonate (4.93 g, 35.7 mmol) and4-fluorobenzyl bromide (1.62 g, 0.746 mL, 8.56 mmol) was added. Thereaction was heated at 50° C. for 4 hours. The reaction was cooled andthe inorganics were separated via filtration. The filter cake was washedthrough with ethyl acetate (2×10 mL) and the combined washings andfiltrate were concentrated in vacuo.

The residue was refluxed in methanol (10 mL) containing potassiumhydroxide (0.8 g, 14.28 mmol), for 18 hours. The reaction was cooled andconcentrated in vacuo. The residue was dissolved in H₂O and washed withdichloromethane. The aqueous layer was separated and carefully acidifiedusing an aqueous 6N hydrochloric acid solution. The resultingprecipitate was filtered, washed with copious amounts of water and driedin vacuo to afford the title compound, 1.05 g, 67%.

The title compound, Example 21, was purified by trituration withacetonitrile, and isolated as a green solid, 80 mg, 51%.

LC/MS: RT=1.14 Min (270 nm), m/z=428 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 5.44 (s, 2H), 6.96-7.01 (m, 1H), 7.05-7.20 (m, 5H),7.40-7.47 (m, 1H), 7.49-7.55 (m, 2H), 7.80-7.84 (m, 1H), 8.06 (s, 1H),8.18 (d, 1H), 8.44 (s, 1H), 9.80 (s, 1H), 11.56 (br s, 1H), 12.01 (br s,1H).

Example 22 1-(3-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6,following the same experimental procedures as for Examples 20 and 21.

LC/MS: RT=1.14 Min (270 nm), m/z=428 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 5.44 (s, 2H), 6.96-7.01 (m, 1H), 7.05-7.22 (m, 5H),7.40-7.47 (m, 1H), 7.50-7.55 (m, 2H), 7.82 (m, 1H), 8.06 (s, 1H), 8.19(d, 1H), 8.45 (s, 1H), 9.81 (s, 1H), 11.56 (br s, 1H), 12.02 (br s, 1H).

Example 23 1-(3-Trifluoromethyl-benzyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6,following the same experimental procedures as for Examples 20 and 21.

LC/MS: RT=1.21 Min (270 nm), m/z=478 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 5.53 (s, 2H), 6.96-7.01 (m, 1H), 7.05-7.10 (m, 2H),7.49-7.72 (m, 6H), 7.80-7.84 (m, 1H), 8.07 (s, 1H), 8.18 (d, 1H), 8.48(s, 1H), 9.80 (s, 1H), 11.56 (br s, 1H), 12.02 (br s, 1H).

Example 24 1-(3,4-Difluoro-benzyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6,following the same experimental procedures as for Examples 20 and 21.

LC/MS: RT=1.16 Min (270 nm), m/z=446 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 5.41 (s, 2H), 6.96-7.01 (m, 1H), 7.05-7.10 (m, 2H),7.12-7.18 (m, 1H), 7.37-7.55 (m, 4H), 7.81 (d, 1H), 8.05 (s, 1H), 8.19(d, 1H), 8.44 (s, 1H), 9.80 (s, 1H), 11.56 (br s, 1H), 12.01 (br s, 1H).

Example 25 1-(4-Trifluoromethyl-benzyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6,following the same experimental procedures as for Examples 20 and 21.

LC/MS: RT=1.21 Min (270 nm), m/z=478 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 5.54 (s, 2H), 6.95-7.01 (m, 1H), 7.05-7.10 (m, 2H),7.44-7.56 (m, 4H), 7.76 (d, 2H), 8.08 (s, 1H), 8.19 (d, 1H), 8.48 (s,1H), 9.82 (s, 1H), 11.56 (br s, 1H), 11.91 (br s, 1H), NH not seen.

Example 26 1-(3-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6,following the same experimental procedures as for Examples 20 and 21.

LC/MS: RT=2.29 Min (270 nm), m/z=424 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.30 (s, 3H), 5.36 (s, 2H), 6.95-7.01 (m, 1H),7.04-7.17 (m, 5H), 7.24-7.29 (m, 1H), 7.48-7.56 (m, 2H), 7.81 (s, 1H),8.04 (s, 1H), 8.18 (d, 1H), 8.39 (s, 1H), 9.78 (s, 1H), 11.55 (br s,1H), 12.01 (br s, 1H).

Example 27 1-(3-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6,following the same experimental procedures as for Examples 20 and 21.

LC/MS: RT=2.31 Min (270 nm), m/z=444, 446 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 5.43 (s, 2H), 6.95-7.11 (m, 3H), 7.22-7.28 (m, 1H),7.34-7.57 (m, 5H), 7.81 (d, 1H), 8.06 (s, 1H), 8.19 (d, 1H), 8.45 (s,1H), 9.81 (s, 1H), 11.56 (br s, 1H), 12.02 (br s, 1H).

Example 28 1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6,following the same experimental procedures as for Examples 20 and 21.

LC/MS: RT=2.31 Min (270 nm), m/z=444, 446 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 5.41 (s, 2H), 6.96-7.11 (m, 3H), 7.29-7.34 (m, 2H),7.43-7.56 (m, 4H), 7.81 (d, 1H), 8.05 (s, 1H), 8.18 (d, 1H), 8.42 (s,1H), 9.80 (s, 1H), 11.56 (br s, 1H), 12.02 (br s, 1H).

Example 29 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6,following the same experimental procedures as for Examples 20 and 21.

LC/MS: RT=2.28 Min (270 nm), m/z=424 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.29 (s, 3H), 5.35 (s, 2H), 6.94-7.11 (m, 3H), 7.19(m, 4H), 7.48-7.56 (m, 2H), 7.81 (d, 1H), 8.02 (s, 1H), 8.18 (d, 1H),8.37 (s, 1H), 9.77 (s, 1H), 11.56 (br s, 1H), 12.01 (br s, 1H).

Example 30 1-(3-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 7.

Step 1: Preparation of 3-Iodo-6-methyl-5-nitro-1H-pyridin-2-one (7a)

The title compound was prepared according to the experimental used inExample 17, Step 3 using 2-hydroxy-6-methyl-5-nitropyridine. The usualwork up afforded the title compound as a pale yellow solid, 4.95 g, 81%.

Step 2: Preparation of3-Iodo-6-methyl-5-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyridin-2-one(7b)

The title compound was prepared according to the experimental used inExample 1, Step 1, using intermediate (7a),3-iodo-6-methyl-5-nitro-1H-pyridin-2-one. After the usual work up, thecrude product was purified by flash chromatography on SiO₂ eluting firstwith hexane and then 10% ethyl acetate/hexane to firstly afford theundesired oxygen substituted compound and then the desired titlecompound as a yellow oil, 3.6 g, 42%.

Step 3: Preparation of2-[6-Methyl-5-nitro-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (7c)

The title compound was prepared according to the experimental used inExample 17, Step 5, with intermediate 7(b),3-iodo-6-methyl-5-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyridin-2-one.After the usual work up, the crude product was purified by flashchromatography on SiO₂ with hexane—10% ethyl acetate/hexane (gradient)to afford the title compound as a cream coloured solid, 3.46 g, 72%.

Step 4: Preparation of2-[5-Amino-6-methyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (7d)

The title compound was prepared according to the experimental used inExample 20, Step 3 with intermediate (7c),2-[6-methyl-5-nitro-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester. After the usual work up, the crude product waspurified by flash chromatography on SiO₂ with hexane—65% ethylacetate/hexane (gradient) to afford the title compound as a yellow foam,2.27 g, 83%.

Step 5: Preparation of2-[5-{[1-(3-Fluoro-benzyl)-1H-pyrazole-4-carbonyl]-amino}-6-methyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (7e)

The title compound was prepared according to the experimental used inExample 20, Step 4 with intermediate (7d),2-[5-amino-6-methyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydropyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester, and 1-(3-Fluoro-benzyl)-1H-pyrazole-4-carboxylicacid, which was synthesised according to the protocol described forintermediate (6e) in Example 21. The resultant crude product waspurified by flash chromatography on SiO₂ with hexane—50% ethylacetate/hexane (gradient) to afford the title compound as a yellow oil,80 mg, 70%.

Step 6: Preparation of the Title Compound:1-(3-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared according to the experimental fromExample 1, Step 5, with intermediate (7e),2-[5-{[1-(3-fluoro-benzyl)-1H-pyrazole-4-carbonyl]-amino}-6-methyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester. The title compound was purified by triturationwith acetonitrile, and isolated as a pale green solid, 8 mg, 15%.

LC/MS: RT=1.93 Min (270 nm), m/z=442 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.18 (s, 3H), 5.45 (s, 2H) 6.95-7.01 (m, 1H),7.04-7.1 (m, 1H), 7.12-7.22 (m, 4H), 7.42-7.56 (m, 3H), 7.99 (s, 1H),8.07 (s, 1H), 8.46 (s, 1H), 9.57 (s, 1H), 11.45 (br s, 1H), 12.18 (br s,1H).

Example 31 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 7,following the same procedures as for Example 30.

LC/MS: RT=2.15 Min (270 nm), m/z=424 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.16 (s, 3H), 5.40 (s, 2H), 6.96 (t, 1H), 7.05 (t,1H), 7.16 (s, 1H), 7.29-7.40 (m, 5H), 7.44 (d, 1H), 7.49 (d, 1H), 7.96(s, 1H), 8.03 (s, 1H), 8.40 (s, 1H), 9.50 (s, 1H), 11.42 (s, 1H), 12.14(br s, 1H).

Example 32 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 7,following the same procedures as for Example 30.

LC/MS: RT=2.18 Min (270 nm), m/z=442 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.16 (s, 3H), 5.40 (s, 2H), 6.96 (t, 1H), 7.05 (t,1H), 7.16 (s, 1H), 7.19-7.39 (m, 4H), 7.44 (d, 1H), 7.49 (d, 1H), 7.95(s, 1H), 8.03 (s, 1H), 8.40 (s, 1H), 9.50 (s, 1H), 11.42 (s, 1H), 12.14(br s, 1H).

Example 33 1-(3,4-Difluoro-benzyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 7,following the same procedures as for Example 30.

LC/MS: RT=2.21 Min (270 nm), m/z=460 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.16 (s, 3H), 5.40 (s, 2H), 6.96 (t, 1H), 7.05 (t,1H), 7.16 (m, 2H), 7.38-7.50 (m, 4H), 7.96 (s, 1H), 8.05 (s, 1H), 8.42(s, 1H), 9.52 (s, 1H), 11.43 (s, 1H), 12.15 (br s, 1H).

Example 34 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid (1-cyclohexylmethyl-1H-pyrazol-4-yl)-amide

The title compound was prepared according to the general route outlinedin Scheme 1.

LC/MS: RT=2.20 Min (270 nm), m/z=416 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.92-1.02 (m, 2H), 1.15-1.26 (m, 3H) 1.53 (d, 2H),1.6-1.72 (m, 3H), 1.75-1.85 (m, 1H), 3.95 (d, 2H), 6.99-7.03 (m, 1H),7.09-7.13 (m, 1H), 7.28 (d, 1H), 7.51 (d, 1H), 7.56-7.59 (m, 2H), 7.99(s, 1H), 8.13 (br s, 1H), 8.59 (d, 1H), 10.28 (brs, 1H), 11.52 (br s,1H), 12.49 (br s, 1H).

Example 35 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid (1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-amide

The title compound was prepared according to the general route outlinedin Scheme 1.

LC/MS: RT=1.83 Min (270 nm), m/z=409 [M−H]. Total run time 3.75 min(short pos/neg).

¹H NMR (d₆ DMSO): δ 5.38 (s, 2H), 6.98 (td, 1H), 7.10 (td, 1H), 7.24 (d,1H), 7.38 (ddd, 1H), 7.48 (dd, 1H), 7.54 (d, 1H), 7.62 (d, 1H), 7.65(dt, 1H), 8.11 (d, 1H), 8.17 (s, 1H), 8.51 (m, 2H), 8.56 (d, 1H), 10.31(s, 1H), 11.52 (br s, 1H), 12.50 (br s, 1H).

Example 36 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid (1-pyridin-4-ylmethyl-1H-pyrazol-4-yl)-amide

The title compound was prepared according to the general route outlinedin Scheme 1.

LC/MS: RT=1.78 Min (270 nm), m/z=411 [M+H]. Total run time 3.75 min(short pos/neg).

¹H NMR (d₆ DMSO): δ 5.41 (s, 2H), 6.98 (td, 1H), 7.09 (t, 1H), 7.12 (d,2H), 7.25 (d, 1H), 7.48 (d, 1H), 7.54 (d, 1H), 7.66 (s, 1H), 8.13 (d,1H), 8.19 (s, 1H), 8.53 (m, 2H), 8.55 (d, 1H), 10.34 (s, 1H), 11.53 (brs, 1H), 12.45 (br s, 1H)

Example 37 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-fluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared according to the route outlined inScheme 8.

Step 1: Preparation of (1H-Indol-5-yl)-methanol (8a)

To a mechanically stirred solution of indole-5-carboxylic acid (26.3 g,163 mmol) in tetrahydrofuran (600 mL), was added a solution of lithiumaluminium hydride 1.0M in tetrahydrofuran (200 mL, 200 mmol) drop wiseat ambient temperature. A solution of lithium aluminium hydride 2.0M intetrahydrofuran (22 mL, 44 mmol) was added drop wise at ambienttemperature, and then the reaction mixture was carefully heated up toreflux and held there for 1 hour. The reaction mixture was cooled toambient temperature and then water (13 mL) was added drop wise, followedby an aqueous 10% sodium hydroxide solution (13 mL), and water (20 mL).The suspension was stirred at ambient temperature for 30 minutes,filtered through a bed of celite and the filter cake washed with ethylacetate (2×200 mL). The filtrate and the washings were combined and theorganics were separated, dried (Na₂SO₄) and concentrated in vacuo, togive a dark red oil. The resultant crude product was suspended in hexane(200 mL), and ethyl acetate (10 mL) was added. This mixture was stirredat ambient temperature for 18 hours, and the solids were separated viafiltration and washed with hexane to afford the title compound as alight brown solid, 22.25 g, 93%.

Step 2: Preparation of5-(tert-Butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acidtert-butyl ester (8b)

To a mechanically stirred solution of (1H-Indol-5-yl)-methanol, (8a),(22.2 g, 151 mmol) in dichloromethane (300 mL) at ambient temperaturewas added N,N-diisopropylethylamine (39.0 g, 52.6 mL, 302 mmol) followedby a solution of tert-butyldimethylsilyl chloride (25 g, 166 mmol) indichloromethane (400 mL). 4-Dimethylaminopyridine (1.84 g, 15.1 mmol)was added and the reaction was stirred at ambient temperature for 2hours. The reaction mixture was concentrated in vacuo and the residuewas taken up in ethyl acetate (400 mL), washed with an aqueous 0.5Nhydrochloric acid solution (600 mL), brine, dried (Na₂SO₄) andconcentrated in vacuo to yield a red oil.

This red oil was dissolved in dichloromethane (350 mL) and to this wasadded di-tert-butyl dicarbonate (36.2 g, 166 mmol) drop wise at ambienttemperature as a solution in dichloromethane (50 mL).4-Dimethylaminopyridine (1.84 g, 15.1 mmol) was added and the reactionstirred at ambient temperature for 2 hours. The reaction mixture wasconcentrated in vacuo and the residue was taken up in ethyl acetate (300mL), washed with an aqueous 0.5N hydrochloric acid solution (200 mL),brine, dried (Na₂SO₄) and concentrated in vacuo to yield a light brownoil. The resultant crude product was purified by flash chromatography onSiO₂ eluting first with hexane and then 10% ethyl acetate/hexane toafford the desired title compound as a white solid, 52.22 g, 96%.

Step 3: Preparation of5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-[3-nitro-6-oxo-5-(2-trimethylsilanyl-ethoxymethyl)-cyclohexa-,3-dienyl]-indole-1-carboxylicacid tert-butyl ester (8c)

To a solution of diisopropylamine (2.1 g, 2.89 mL, 20.8 mmol) inanhydrous tetrahydrofuran (10 mL) was added butyllithium solution 2.5Min hexanes (7.71 mL, 19.3 mmol) drop wise at −78° C. After addition thereaction mixture was allowed to attain 0° C., where it was stirred for30 minutes to form the lithiumdiisopropyl amide solution.

5-(tert-Butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acidtert-butyl ester (8b) (5.89 g, 16.3 mmol) was stirred in tetrahydrofuran(80 mL) and triisopropyl borate (4.18 g, 5.13 mL, 22.2 mmol) was added,and the reaction mixture was cooled to −5° C. To this was added thepreviously described lithiumdiisopropyl amide solution drop wise keepingthe temperature between −5° C. and 0° C. After addition the reaction wasstirred at −5° C. for 30 mins and then allowed to attain ambienttemperature. The reaction mixture was concentrated in vacuo to yieldcrude indole-2-boronicacid-5-(tert-Butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acidtert-butyl ester, which was dissolved in tetrahydrofuran (100 mL). Water(20 mL), potassium carbonate (6.17 g, 44.6 mmol),3-iodo-5-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyridin-2-one,intermediate (6a) (5.87 g, 14.8 mmol) in tetrahydrofuran (20 mL) and[1,1-Bis(diphenylphosphino)ferrocene)]dichloropalladium(11), complexwith dichloromethane (0.605 g, 5 mol %) were added. The red suspensionwas degassed for 10 minutes and then heated at 60° C. for 2 hours. Thereaction mixture was cooled and was partitioned between ethyl acetate(200 mL) and aqueous saturated sodium bicarbonate solution (200 mL). Theorganic layer was separated and the aqueous was extracted with a furtherportion of ethyl acetate. The combined ethyl acetate layers were washedwith brine, dried (Na₂SO₄), filtered through a plug of celite andconcentrated in vacuo. The resultant crude product was purified by flashchromatography on SiO₂ eluting with hexane—15% ethyl acetate/hexane(gradient) to afford the desired title compound as a yellow solid, 8.44g, 90%.

Step 4: Preparation of2-[5-Amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(tert-butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylicacid tert-butyl ester (8d)

The title compound was prepared by the route outlined in Scheme 8 andusing the experimental from Example 20, Step 3, with intermediate (8c)5-(tert-butyl-dimethyl-silanyloxymethyl)-2-[3-nitro-6-oxo-5-(2-trimethylsilanyl-ethoxymethyl)-cyclohexa-,3-dienyl]-indole-1-carboxylicacid tert-butyl ester (11.58 g, 18.4 mmol).

The resultant crude product was purified by flash chromatography on SiO₂with hexane—50% ethyl acetate/hexane (gradient) to afford the titlecompound as a dark yellow foam, 10.21 g, 93%.

Step 5: Preparation of5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (8e)

The title compound was prepared by the route outlined in Scheme 8 andusing the experimental from Example 20, step 4, with intermediate (8d),2-[5-amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(tert-butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylicacid tert-butyl ester (1.0 g, 1.67 mmol) and1-(4-methyl-benzyl)-1H-pyrazole-4-carboxylic acid (0.43 g, 1.99 mmol)which had been synthesised according to the protocol described forintermediate (6e) in example 21.

The resultant crude product was purified by flash chromatography on SiO₂with hexane—50% ethyl acetate/hexane (gradient) to afford the titlecompound as a pink oil, 0.721 g, 54%.

Step 6: Preparation of5-Formyl-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (8f)

Intermediate 8(e),5-(tert-butyl-dimethyl-silanyloxymethyl)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (0.72 g, 0.9 mmol) was stirred in tetrahydrofuran(20 mL) and cooled to 0° C. Tetrabutylammonium fluoride solution 1.0M intetrahydrofuran (0.9 mL, 0.9 mmol) was added drop wise at 0° C., andthen the reaction was allowed to attain ambient temperature, where itwas stirred for a further 2 hours. The reaction mixture was diluted withethyl acetate (30 mL), washed with water (30 mL), aqueous 0.5Nhydrochloric acid solution (30 mL), brine, dried (Na₂SO₄) andconcentrated in vacuo to yield a green foam.

This green foam was dissolved in anhydrous dichloromethane (20 mL) andmanganese dioxide (1.17 g, 13.5 mmol) was added. The reaction wasrefluxed for 1 hour and, after cooling, the mixture was filtered througha bed of celite. The filter cake was washed through with tetrahydrofuran(20 mL) and the filtrate was concentrated in vacuo. The resultant crudeproduct was purified by flash chromatography on SiO₂ with hexane—50%ethyl acetate/hexane (gradient) to afford the title compound as a tansolid, 0.454 g, 74%.

Step 7: Preparation of5-(4-Fluoro-piperidin-1-ylmethyl)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (8g)

To a solution of intermediate (8f),5-Formyl-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester, (150 mg, 0.22 mmol) in dichloromethane (10 mL)was added 4-fluoropiperidine hydrochloride (61 mg, 0.44 mmol), sodiumtriacetoxyborohydride (140 mg, 0.66 mmol) and acetic acid (1 drop). Thereaction mixture was stirred at ambient temperature for 3 hours and thendiluted with ethyl acetate. The mixture was washed with saturatedaqueous sodium bicarbonate solution, brine, dried (Na₂SO₄) andconcentrated in vacuo. The resultant crude product was purified by flashchromatography on SiO₂ with hexane-ethyl acetate (gradient) and then ionexchange using an SCX-2 column to afford the title compound as a yellowsolid, 96 mg, 57%.

Step 8: Preparation of the Title Compound:1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-fluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

A 2-5 mL microwave vial was charged with intermediate (8g),5-(4-fluoro-piperidin-1-ylmethyl)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4carbonyl]amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indolecarboxylicacid tert-butyl ester (96 mg, 0.125 mmol), tetrahydrofuran (3 mL),1,2-diaminoethane (38 mg, 42 ul, 0.63 mmol) and finallytetrabutylammonium fluoride solution 1.0M in tetrahydrofuran (0.63 mL,0.63 mmol). The vial was heated under microwave irradiation at 120° C.for 20 mins. After cooling, the reaction mixture was diluted with ethylacetate (20 mL) and washed with water (4×20 mL) and brine (4×20 mL). Theorganics were dried (Na₂SO₄) and concentrated in vacuo. The resultantyellow solid was purified via trituration using acetonitrile, to affordthe title compound as a yellow solid, 42 mg, 63%.

LC/MS: RT=1.51 Min (270 nm), m/z=539 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.66-1.88 (m, 4H), 2.26-2.32 (m, 5H), 2.55 (m, 2H),3.50 (s, 2H), 4.59-4.75 (m, 1H), 5.34 (s, 2H), 7.00-7.05 (m, 2H), 7.19(m, 4H), 7.41 (s, 1H), 7.44 (d, 1H), 7.81 (d, 1H), 8.01 (s, 1H), 8.16(d, 1H), 8.36 (s, 1H), 9.76 (s, 1H), 11.50 (s, 1H), 11.96 (br s, 1H).

Example 38 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[6-oxo-5-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37. It waspurified by trituration with acetonitrile, and isolated as a yellowsolid, 70 mg, 66%.

LC/MS: RT=1.51 Min (270 nm), m/z=521 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.37-1.48 (m, 6H), 2.29-2.33 (m, 7H), 3.45 (s, 2H),5.34 (s, 2H), 7.00-7.04 (m, 2H), 7.19 (m, 4H), 7.40-7.44 (d, 2H), 7.81(d, 1H), 8.01 (s, 1H), 8.16 (d, 1H), 8.36 (s, 1H), 9.76 (s, 1H), 11.49(s, 1H), 11.96 (br s, 1H).

Example 39 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-hydroxymethyl-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37.

The crude product was purified by flash chromatography on SiO₂ withdichloromethane—40% methanol/dichloromethane (gradient) and thentrituration with diethyl ether to afford the title compound as a yellowsolid, 9 mg, 13%.

LC/MS: RT=1.44 Min (270 nm), m/z=551 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.06-1.15 (m. 2H), 1.32 (m, 1H), 1.59 (m, 2H), 1.86(m, 2H), 2.29 (s, 3H), 2.81 (m, 2H), 3.22 (m, 2H), 3.46 (s, 2H), 4.36(t, 1H), 5.34 (s, 2H), 6.99-7.03 (m, 2H), 7.19 (m, 4H), 7.39-7.43 (d,2H), 7.81 (d, 1H), 8.01 (s, 1H), 8.15 (d, 1H), 8.36 (s, 1H), 9.76 (s,1H), 11.50 (s, 1H), NH not seen.

Example 40 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[5-(5-morpholin-4-ylmethyl-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 39 mg, 51%.

LC/MS: RT=1.41 Min (270 nm), m/z=523 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.29 (s, 3H), 2.36 (m, 4H), 3.49 (s, 2H), 3.56 (m,4H), 5.34 (s, 2H), 7.00-7.05 (m, 2H), 7.19 (m, 4H), 7.43-7.46 (d, 2H),7.82 (d, 1H), 8.01 (s, 1H), 8.16 (d, 1H), 8.36 (s, 1H), 9.76 (s, 1H),11.51 (s, 1H), 11.97 (br s, 1H).

Example 41 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[6-oxo-5-(5-pyrrolidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 35 mg, 56%.

LC/MS: RT=1.47 Min (270 nm), m/z=507 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.68 (m, 4H), 2.29 (s, 3H), 2.43 (m, 4H), 3.61 (s,2H), 5.34 (s, 2H), 7.00-7.05 (m, 2H), 7.19 (m, 4H), 7.42-7.44 (d, 2H),7.82 (d, 1H), 8.01 (s, 1H), 8.16 (d, 1H), 8.36 (s, 1H), 9.75 (s, 1H),11.49 (s, 1H), 11.96 (br s, 1H).

Example 42 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(3-hydroxy-azetidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 18 mg, 40%.

LC/MS: RT=1.42 Min (270 nm), m/z=509 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.29 (s, 3H), 2.74 (m, 2H), 3.44 (m, 2H), 3.57 (s,2H), 4.16 (m, 1H), 5.23 (d, 1H), 5.34 (s, 2H), 6.97-7.02 (m, 2H), 7.19(m, 4H), 7.38-7.42 (d, 2H), 7.81 (d, 1H), 8.01 (s, 1H), 8.15 (d, 1H),8.36 (s, 1H), 9.75 (s, 1H), 11.49 (s, 1H), 11.90 (br s, 1H).

Example 43 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[5-(5-{[(2-hydroxy-ethyl)-methyl-amino]-methyl}-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 37 mg, 50%.

LC/MS: RT=1.42 Min (270 nm), m/z=511 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.15 (s, 3H), 2.29 (s, 3H), 2.43 (t, 2H), 3.48-3.55(m, 4H), 4.32 (t, 1H), 5.35 (s, 2H), 7.00-7.05 (m, 2H), 7.19 (m, 4H),7.42-7.44 (d, 2H), 7.82 (d, 1H), 8.01 (s, 1H), 8.15 (d, 1H), 8.36 (s,1H), 9.75 (s, 1H), 11.49 (s, 1H), 11.96 (br s, 1H).

Example 44 1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid[6-oxo-5-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37.

The title compound was purified by flash chromatography on SiO₂ withdichloromethane—12% methanol/dichloromethane—12% methanol/2% ammoniasolution 7N in methanol/dichloromethane (gradient) and isolated as ayellow solid, 2.1 mg, 12%.

LC/MS: RT=0.93 Min (270 nm), m/z=541 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.24-1.26 (m, 2H), 1.34-1.39 (m, 2H), 1.48-1.49 (m,4H), 2.32-2.36 (m, 2H), 3.45-3.51 (m, 2H), 5.41 (s, 2H), 7.01 (d, 1H),7.04 (dd, 1H), 7.31 (d, 2H), 7.41-7.42 (m, 4H), 7.82 (d, 1H), 8.04 (s,1H), 8.17 (d, 1H), 8.42 (s, 1H), 9.79 (1H, s), 11.51 (1H, s), NH notseen.

Example 45 1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid[5-(5-{[ethyl-(2-hydroxy-ethyl)-amino]-methyl}-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37.

The resultant crude product was purified by trituration withacetonitrile to afford the title compound as brown solid, 8 mg, 20%

LC/MS: RT=0.91 Min (270 nm), m/z=545 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.27 (t, 3H), 3.11-3.18 (m, 4H), 3.66-3.75 (m, 2H),4.38 (d, 2H), 5.39 (s, 2H), 7.11 (s, 1H), 7.22 (dd, 1H), 7.30 (d, 2H),7.41 (d, 2H), 7.58 (d, 1H), 7.72 (s, 1H), 7.83 (d, 1H), 8.03 (s, 1H),8.26 (d, 1H), 8.40 (s, 1H), 9.18 (s, 1H), 9.80 (s, 1H), 11.76 (s, 1H),NH not seen.

Example 46 1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid(5-{5-[(2-hydroxy-ethylamino)-methyl]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37.

The resultant crude product was taken up in methanol (1 mL) and loadedonto a 5 g SCX column. The column was flushed with methanol and theneluted with ammonia solution 7N in methanol. The eluent was concentratedin vacuo and the residue further purified by preparative HPLC at pH 4 toafford the title compound as a yellow solid, 3 mg, 8%.

LC/MS: RT=0.90 Min (270 nm), m/z=456 [Fragment]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 2.90-2.93 (m, 2H), 3.63 (m, 2H), 4.15 (s, 2H), 5.10(s, 1H), 5.41 (s, 2H), 7.09 (d, 1H), 7.20 (dd, 1H), 7.31 (d, 2H), 7.50(d, 2H), 7.55 (d, 1H), 7.66 (s, 1H), 7.80 (d, 1H), 8.05 (s, 1H), 8.25(d, 1H), 8.43 (s, 1H), 9.82 (s, 1H), 11.68 (s, 1H), NHs not seen.

Example 47 1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-fluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37.

The title compound was purified by flash chromatography on SiO₂ withdichloromethane—10% methanol/dichloromethane—10% methanol/1% ammoniasolution 7N in methanol/dichloromethane (gradient) and isolated as ayellow solid, 30 mg, 65%.

LC/MS: RT=1.73 Min (270 nm), m/z=560, 561 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.23 (m, 2H), 1.69 (m, 2H), 1.79-1.86 (m, 2H),2.29-2.33 (m, 2H), 3.51 (s, 2H), 4.61-4.73 (m, 1H), 5.41 (s, 2H), 7.01(d, 1H), 7.04 (dd, 1H), 7.31 (d, 2H), 7.42-7.46 (m, 4H), 7.82 (d, 1H),8.04 (s, 1H), 8.17 (d, 1H), 8.41 (s, 1H), 9.78 (s, 1H), 11.51 (s, 1H),11.98 (s, 1H).

Example 48 1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-hydroxy-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37.

It was purified by flash chromatography on SiO₂ with dichloromethane—10%methanol/dichloromethane—10% methanol/1% ammonia solution 7N inmethanol/dichloromethane (gradient) and then by trituration withacetonitrile. The desired compound was isolated as a yellow solid, 8 mg,10%.

LC/MS: RT=0.91 Min (270 nm), m/z=557 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.36-1.39 (m, 2H), 1.68-1.71 (m, 2H), 2.01 (m, 2H),2.67 (m, 2H), 3.46 (m, 2H), 4.51 (s, 1H), 5.41 (s, 2H), 7.01-7.03 (m,2H), 7.31 (d, 2H), 7.44 (m, 4H), 7.82 (d, 1H), 8.04 (s, 1H), 8.17 (d,1H), 8.42 (s, 1H), 9.78 (s, 1H), 11.50 (s, 1H), 11.98 (s, 1H), OH notseen.

Example 49 1-Benzyl-1H-pyrazole-4-carboxylic acid{3-[5-(4-fluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37.

Purification by trituration with acetonitrile afforded the titlecompound as a yellow solid, 51 mg, 85%

LC/MS: RT=0.91 Min (270 nm), m/z=525 [M+H]. Total run time 1.9 min(super short pos/neg).

¹H NMR (d₆ DMSO): δ 1.68 (m, 2H), 1.78 (m, 2H), 2.26 (m, 2H), 2.60 (m,2H), 3.50 (s, 2H), 4.66 (dm, 1H), 5.40 (s, 2H), 6.99 (d, 1H), 7.02 (dd,1H), 7.40 (m, 7H), 7.85 (d, 1H), 8.07 (s, 1H), 8.25 (d, 1H), 8.46 (s,1H), 9.92 (s, 1H), 11.51 (br s, 1H), 11.96 (br s, 1H)

Example 50 1-Benzyl-1H-pyrazole-4-carboxylic acid[6-oxo-5-(5-pyrrolidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37.

Purification by trituration with acetonitrile afforded the titlecompound as a yellow solid, 38 mg, 46%

LC/MS: RT=0.90 Min (270 nm), m/z=493 [M+H]. Total run time 1.9 min(super short pos/neg).

¹H NMR (d₆ DMSO): δ 1.68 (br s, 4H), 2.43 (br s, 4H), 3.61 (br s, 2H),5.40 (s, 2H), 6.99 (d, 1H), 7.04 (dd, 1H), 7.38 (m, 7H), 7.84 (d, 1H),8.06 (s, 1H), 8.22 (br s, 1H), 8.44 (s, 1H), 9.87 (s, 1H), 11.49 (s,1H), 11.96 (br s, 1H)

Example 51 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(5-morpholin-4-ylmethyl-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37, with aslight modification to the protocol in Step 5.

Step 5: Preparation of5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (8e)

Intermediate (8d),2-[5-amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(tert-butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylicacid tert-butyl ester, (600 mg, 1 mmol) was stirred in dichloromethane(50 mL) at RT with triethylamine (202 mg, 0.278 mL, 2 mmol). Thereaction mixture was cooled to 5° C. and then a solution of1-Benzyl-1H-pyrazole-4-carbonyl chloride (265 mg, 1.2 mmol), which hadbeen prepared according to the protocol below, in dichloromethane (10ml), was added drop wise. After addition the reaction was stirred at RTfor 18 hrs and then the reaction mixture was washed with saturatedsodium hydrogen carbonate solution (2×50 mL), brine (50 ml), dried(Na₂SO₄) and concentrated in vacuo. The resultant crude product waspurified by flash chromatography on SiO₂ eluting with hexane—50% ethylacetate/hexane (gradient) to afford the desired compound as a pale greenfoam, 750 mg, 96%.

Preparation of 1-Benzyl)-1H-pyrazole-4-carbonyl chloride used in Step 5,above. 1-Benzyl-1H-pyrazole-4-carboxylic acid (1.6 g, 7.92 mmol) wasstirred as a suspension in toluene (20 mL) at RT and thionyl chloride(1.88 g, 1.15 mL, 15.8 mmol) was added. The reaction mixture was slowlyheated to reflux and heating continued for 4 hrs. After cooling thereaction was concentrated in vacuo. Toluene was added to the residue andconcentrated in vacuo. This was repeated a further three times withtoluene and twice with isohexane. The crude oil obtained was usedwithout further purification, 1.65 g, 95%.

The title compound was purified by trituration with acetonitrileafforded the title compound as a yellow solid, 25 mg, 36%

LC/MS: RT=1.64 Min (270 nm), m/z=509 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.29-2.39 (m, 4H), 3.50 (s, 2H), 3.52-3.60 (m, 4H),5.41 (s, 2H), 7.00-7.02 (m, 2H), 7.28-7.46 (m, 7H), 7.82 (s, 1H), 8.04(s, 1H), 8.16-8.19 (d, 1H), 8.40 (s, 1H), 9.77 (s, 1H), 11.51 (s, 1H),11.96 (br s, 1H).

Example 52 1-Benzyl-1H-pyrazole-4-carboxylic acid[6-oxo-5-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 0.467 g, 42%.

LC/MS: RT=1.44 Min (270 nm), m/z=507 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.37 (m, 2H), 1.47 (m, 4H), 2.32 (m, 4H), 3.45 (s,2H), 5.41 (s, 2H), 7.00-7.03 (m, 2H), 7.28-7.44 (m, 7H), 7.82 (d, 1H),8.03 (s, 1H), 8.16 (d, 1H), 8.41 (s, 1H), 9.79 (s, 1H), 11.50 (s, 1H),11.99 (br s, 1H).

Example 53 1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-methyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by preparative HPLC at pH9 and isolatedas a yellow solid, 3 mg, 4%.

LC/MS: RT=1.64 Min (270 nm), m/z=556 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.14 (s, 3H), 2.20-2.40 (m, 8H), 3.48 (s, 2H), 5.41(s, 2H), 7.0-7.48 (m, 8H), 7.81 (d, 1H), 8.04 (s, 1H), 8.16 (d, 1H),8.42 (s, 1H), 9.78 (s, 1H), 11.50 (s, 1H), 11.92 (br s, 1H).

Example 54 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-[(2-hydroxy-ethylamino)-methyl]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 5 mg, 9%.

LC/MS: RT=1.41 Min (270 nm), m/z=497 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.29 (s, 3H), 2.60 (q, 2H), 3.47 (q, 2H), 3.75 (s,2H), 4.45 (t, 1H), 5.34 (s, 2H), 7.00 (s, 1H), 7.05 (d, 1H), 7.19 (m,4H), 7.41-7.45 (m, 2H), 7.82 (d, 1H), 8.01 (s, 1H), 8.16 (d, 1H), 8.36(s, 1H), 9.75 (s, 1H), 11.48 (s, 1H).

Example 55 1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid[6-oxo-5-(5-pyrrolidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 33 mg, 49%.

LC/MS: RT=0.96 Min (270 nm), m/z=527 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.62 (m, 4H), 2.40-2.48 (m, 4H), 3.60 (s, 2H), 5.41(s, 2H), 6.96-7.46 (m, 8H), 7.80-7.84 (d, 1H), 8.04 (s, 1H), 8.17 (d,1H), 8.42 (s, 1H), 9.78 (s, 1H), 11.50 (s, 1H), 11.90-12.00 (br s, 1H).

Example 56 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(5-{[ethyl-(2-hydroxy-ethyl)-amino]-methyl}-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 13 mg, 17%.

LC/MS: RT=0.88 Min (270 nm), m/z=511 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 0.97-1.01 (t, 3H), 3.41-3.47 (q, 2H), 3.60 (s, 2H),4.24-4.27 (t, 1H), 5.41 (s, 2H), 6.99-7.44 (m, 9H), 7.81-7.82 (d, 1H),8.03 (s, 1H), 8.16-8.17 (d, 1H), 8.41 (s, 1H), 9.78 (s, 1H), 11.51 (s,1H), 11.90-11.98 (br s, 1H).

Example 57 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(3-fluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 25 mg, 33%.

LC/MS: RT=0.91 Min (270 nm), m/z=525 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.40-1.60 (m, 2H), 1.64-1.73 (m, 1H), 1.76-1.80 (m,1H), 2.17-2.25 (m, 1H), 2.26-2.36 (m, 1H), 2.40-2.47 (m, 1H), 2.64-2.76(m, 1H), 3.49-3.59 (d, 2H), 4.51-4.69 (m, 1H), 5.41 (s, 2H), 7.01-7.46(m, 9H), 7.81-7.82 (d, 1H), 8.03 (s, 1H), 8.16-8.17 (d, 1H), 8.40 (s,1H), 9.77 (s, 1H), 11.53 (s, 1H), 11.85-11.95 (br s, 1H).

Example 58 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(4-methyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-31}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 34 mg, 47%.

LC/MS: RT=1.55 Min (270 nm), m/z=522 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.14 (s, 3H), 2.24-2.41 (m, 8H), 3.48 (s, 2H), 5.41(s, 2H), 7.00-7.44 (m, 9H), 7.81-7.82 (d, 1H), 8.03 (s, 1H), 8.16-8.18(d, 1H), 8.41 (s, 1H), 9.78 (s, 1H), 11.52 (s, 1H), 11.94-11.96 (br s,1H).

Example 59 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-methyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 63 mg, 62%.

LC/MS: RT=1.39 Min (270 nm), m/z=536 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.14 (s, 3H), 2.26-2.44 (m, 11H), 3.48 (s, 2H), 5.34(s, 2H), 7.00-7.03 (m, 2H), 7.19 (m, 4H), 7.41-7.44 (m, 2H), 7.82 (d,1H), 8.01 (s, 1H), 8.16 (d, 1H), 8.36 (s, 1H), 9.76 (s, 1H), 11.50 (s,1H), 11.97 (br s, 1H).

Example 60 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(4-hydroxy-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 18 mg, 35%.

LC/MS: RT=1.59 Min (270 nm), m/z=523 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.30-1.43 (m, 2H), 1.64-1.73 (m, 2H), 1.97-2.03 (t,2H), 2.63-2.72 (m, 2H), 3.40-3.44 (m, 1H), 3.46 (s, 2H), 4.49-4.50 (d,1H), 5.41 (s, 2H), 6.99-7.43 (m, 9H), 7.82-7.84 (d, 1H), 8.03 (s, 1H),8.16-8.17 (d, 1H), 8.41 (s, 1H), 9.78 (s, 1H), 11.58 (s, 1H), 11.90 (brs, 1H).

Example 61 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-{5-[(2-hydroxy-ethylamino)-methyl]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 8 mg, 15%.

LC/MS: RT=1.58 Min (270 nm), m/z=422 [Fragment]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.57-2.61 (t, 2H), 3.45-3.49 (m, 2H), 3.74 (s, 2H),4.39-4.46 (m, 1H), 5.41 (s, 2H), 6.99-7.45 (m, 9H), 7.82-7.83 (d, 1H),8.03 (s, 1H), 8.17-8.18 (d, 1H), 8.41 (s, 1H), 9.78 (s, 1H), 11.51 (s,1H).

Example 62 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid(5-{5-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 26 mg, 23%.

LC/MS: RT=1.38 Min (270 nm), m/z=566 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.29 (s, 3H), 2.32-2.45 (m, 10H), 3.44-3.48 (m, 4H),4.32 (t, 1H), 5.34 (s, 2H), 7.00-7.03 (m, 2H), 7.19 (m, 4H), 7.41-7.44(m, 2H), 7.82 (d, 1H), 8.01 (s, 1H), 8.16 (d, 1H), 8.36 (s, 1H), 9.76(s, 1H), 11.50 (s, 1H), 11.96 (br s, 1H).

Example 63 1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(3-fluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by preparative HPLC at pH9 and isolatedas a yellow solid, 4 mg, 6%.

LC/MS: RT=0.95 Min (270 nm), m/z=559 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.39-1.55 (m, 2H), 1.64-1.73 (m, 1H), 1.76-1.89 (m,1H), 2.19-2.25 (m, 1H), 2.28-2.35 (m, 1H), 2.41-2.46 (m, 1H), 2.64-2.76(m, 1H), 3.54-3.55 (d, 2H), 4.50-4.70 (m, 1H), 5.41 (s, 2H), 7.00-7.48(m, 8H), 7.82-7.83 (d, 1H), 8.04 (s, 1H), 8.17-8.18 (d, 1H), 8.42 (s,1H), 9.79 (s, 1H), 11.52 (s, 1H), 11.93-12.02 (br s, 1H).

Example 64 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(4,4-difluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 17 mg, 48%.

LC/MS: RT=0.94 Min (270 nm), m/z=422 [other]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.90-1.99 (m, 4H), 3.56 (s, 2H), 5.41 (s, 2H),7.01-7.46 (m, 9H), 7.82-7.83 (d, 1H), 8.04 (s, 1H), 8.19-8.20 (d, 1H),8.42 (s, 1H), 9.82 (s, 1H), 11.54 (s, 1H).

Example 65 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-{5-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by preparative HPLC at pH 4 and isolatedas a yellow solid, 4 mg, 5%.

LC/MS: RT=0.85 Min (270 nm), m/z=552 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₄ MeOD): δ 2.74-3.13 (m, 10H), 3.70-3.73 (t, 2H), 3.97 (s, 2H),5.40 (s, 2H), 7.05-7.58 (m, 9H), 7.90-7.91 (d, 1H), 8.05 (s, 1H),8.24-8.25 (d, 1H), 8.50 (s, 1H).

Example 66 1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid(5-{5-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by preparative HPLC at pH9 followed bytrituration with acetonitrile and isolated as a yellow solid, 0.5 mg,1%.

LC/MS: RT=0.89 Min (270 nm), m/z=586 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₄ MeOD): δ 2.48-2.71 (m, 8H), 3.62-3.68 (m, 4H), 5.40 (s, 2H),7.02-7.51 (m, 8H), 7.93-7.94 (d, 1H), 8.06 (s, 1H), 8.21-8.22 (d, 1H),8.28 (s, 1H), 8.54 (s, 1H).

Example 67 1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid[5-(5-morpholin-4-ylmethyl-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by preparative HPLC at pH9 and isolatedas a yellow solid, 6 mg, 10%.

LC/MS: RT=0.92 Min (270 nm), m/z=456 [Fragment]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 2.32-2.38 (m, 4H), 3.49 (s, 2H), 3.55-3.57 (m, 4H),5.41 (s, 2H), 7.01-7.05 (m, 2H), 7.28-7.32 (m, 2H), 7.41-7.47 (m, 4H),7.82-7.83 (d, 1H), 8.05 (s, 1H), 8.17-8.18 (d, 1H), 8.42 (s, 1H), 9.81(s, 1H), 11.53 (s, 1H), 11.96-12.04 (br s, 1H).

Example 68 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-1(2-methanesulfonyl-ethylamino)-methyl]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by preparative HPLC at pH9 and isolatedas a yellow solid, 3 mg, 4%.

LC/MS: RT=0.86 Min (270 nm), m/z=422 [Fragment]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 3.13 (s, 3H), 3.52-3.62 (m, 4H), 4.22-4.28 (m, 2H),5.41 (s, 2H), 7.12-7.40 (m, 7H), 7.58-7.60 (d, 1H), 7.69 (s, 1H), 7.80(s, 1H), 8.05 (s, 1H), 8.26-8.27 (d, 1H), 8.43 (s, 1H), 9.85 (s, 1H),11.75 (s, 1H), 12.04-12.11 (br s, 1H).

Example 69 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 2 mg, 10%.

LC/MS: RT=0.92 Min (254 nm), m/z=537 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₄ MeOD): δ 1.10 (d, 6H), 1.76, (t, 2H), 2.79 (d, 2H), 3.58 (s,2H), 3.62-3.72 (m, 2H), 5.4 (s, 2H), 7.01 (s, 1H), 7.12 (dd, 1H),7.28-7.42 (m, 6H), 7.49 (s, 1H), 7.94 (d, 1H), 8.06 (s, 1H), 8.22 (d,1H), 8.25 (s, 1H)

Example 70 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(3,4-dimethyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 17 mg, 23%.

LC/MS: RT=0.87 Min (254 nm), m/z=536 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₄ MeOD): δ 1.03 (d, 3H), 1.91 (t, 1H), 2.15-2.26 (br m, 2H),2.27 (s, 3H), 2.34 (m, 1H), 2.75-2.88 (m, 3H), 3.55-3.63 (m, 2H), 5.4(s, 2H), 7.12 (s, 1H), 8.04-8.1 (dd, 1H), 7.28-7.41 (m, 6H), 7.48 (s,1H), 7.94 (d, 1H), 8.06 (s, 1H), 8.21 (d, 1H), 8.25 (s, 1H).

Example 71 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(cis-2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 84 mg, 62%.

LC/MS: RT=1.56 Min (270 nm), m/z=537 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.00 (d, 6H), 1.62 (m, 2H), 2.68 (m, 2H), 3.47 (s,2H), 3.55 (m, 2H), 5.41 (s, 2H), 7.01-7.04 (m, 2H), 7.28-7.46 (m, 7H),7.82 (d, 1H), 8.03 (s, 1H), 8.16 (d, 1H), 8.41 (s, 1H), 9.79 (s, 1H),11.53 (s, 1H), 11.99 (br s, 1H).

Example 72 1-(4-isopropylbenzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(2,6-dimethylmorpholin-4-ylmethyl)-1H-indol-2-yl)-6-oxo-1,6-dihydropyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by flash chromatography on silicaeluting with dichloromethane/methanol (19:1) to give a pale brown gumfollowed by trituration with diethyl ether, and isolated as a yellowpowder, 30 mg, 23%.

LC/MS: RT=1.76 Min (270 nm), m/z=579 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.10 (br s, 6H), 1.25 (d, 6H), 1.70 (br s, 2H), 2.80(br m, 2H), 2.90 (m, 1H), 3.60 (br m, 3H), 5.40 (s, 2H), 7.10 (br s,1H), 7.30 (m, 3H), 7.50 (br s, 2H), 7.90 (br s, 1H), 8.10 (s, 1H), 8.20(br s, 1H), 8.50 (s, 1H), 9.85 (s, 1H), 11.52 (br s, 1H), 12.00 (br s,1H).

Example 73 1-(4-isopropylbenzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-fluoropiperidin-1-ylmethyl)-1H-indol-2-yl)-6-oxo-1,6-dihydropyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by flash chromatography on silicaeluting with dichloromethane/methanol (19:1) to give a pale brown gumfollowed by trituration with diethyl ether, and isolated as a yellowpowder, 35 mg, 23%.

LC/MS: RT=1.65 Min (270 nm), m/z=567 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.25 (d, 6H), 1.75 (br m, 2H), 1.90 (br m, 2H), 2.35(br m, 2H), 2.90 (m, 1H), 3.60 (s, 2H), 4.70 (br s, 1H), 4.80 (br s,1H), 5.40 (s, 2H), 7.00 (m, 2H), 7.30 (m, 4H), 7.50 (m, 2H), 7.85 (d,1H), 8.10 (s, 1H), 8.20 (d, 1H), 8.45 (s, 1H), 9.85 (s, 1H), 11.54 (brs, 1H), 12.00 (br s, 1H).

Example 74 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(cis-2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 34 mg, 42%.

LC/MS: RT=0.98 Min (270 nm), m/z=551 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.0 (d, 6H), 1.62 (dd, 2H), 2.3 (s, 3H), 2.68 (dd,2H) 3.46 (s, 2H), 3.5-3.6 (m, 2H), 5.35 (s, 2H), 7.0-7.05 (m, 2H), 7.2(s, 4H), 7.40-7.46 (m, 2H), 7.82 (d, 1H), 8.01 (s, 1H), 8.16 (s, 1H),8.37 (s, 1H), 9.79 (br s, 1H), 11.55 (br s, 1H), 11.95 (br s, 1H)

Example 75 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[5-(5-diethylaminomethyl-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 36 mg, 48%.

LC/MS: RT=0.95 Min (270 nm), m/z=509 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 0.98 (q, 6H), 2.28 (s, 3H), 2.46 (q, 4H), 3.55 (s,2H), 5.34 (s, 2H), 7.0 (d, 1H), 7.05 (dd, 1H), 7.19 (s, 4H), 7.41-7.44(m, 2H), 7.81 (d, 1H), 8.01 (s, 1H), 8.15 (s, 1H), 8.37 (s, 1H), 9.78(br s, 1H), 11.5 (br s, 1H), 11.95 (br s, 1H)

Example 76 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(cis-2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 2 mg, 6%.

LC/MS: RT=1.57 Min (270 nm), m/z=555 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.00 (d, 6H), 1.60 (t, 2H), 2.7 (d, 2H), 3.45 (s,2H), 3.55 (m, 2H), 5.40 (s, 2H), 6.89 (br, 1H), 7.00 (dd, 1H), 7.20 (t,2H), 7.40 (m, 4H), 7.82 (d, 1H), 8.05 (s, 1H), 8.15 (br, 1H), 8.40 (s,1H), 9.70 (s, 1H).

Example 77 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-1(cyclohexyl-methyl-amino)-methyl]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 26 mg, 44%.

LC/MS: RT=1.65 Min (270 nm), m/z=535 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.05-1.33 (m, 5H), 1.57 (m, 1H), 1.73-1.81 (m, 4H),2.09 (s, 3H), 2.41 (m, 1H), 3.57 (s, 2H), 5.41 (s, 2H), 6.98-7.04 (m,2H), 7.28-7.43 (m, 7H), 7.82 (d, 1H), 8.03 (s, 1H), 8.15 (d, 1H), 8.41(s, 1H), 9.79 (s, 1H), 11.50 (s, 1H), 11.98 (br s, 1H).

Example 78 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(4-methyl-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 34 mg, 62%.

LC/MS: RT=1.61 Min (270 nm), m/z=521 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.87 (d, 3H), 1.12 (m, 2H), 1.29 (m, 1H), 1.53 (d,2H), 1.87 (t, 2H), 2.78 (d, 2H), 3.46 (s, 2H), 5.41 (s, 2H), 7.00-7.02(m, 2H), 7.28-7.44 (m, 7H), 7.82 (d, 1H), 8.03 (s, 1H), 8.16 (d, 1H),8.41 (s, 1H), 9.79 (s, 1H), 11.50 (s, 1H), 11.99 (br s, 1H).

Example 79 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(5-{1(2-methoxy-ethyl)-methyl-aminol-methyl}-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 20 mg, 31%.

LC/MS: RT=1.52 Min (270 nm), m/z=511 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.15 (s, 3H), 2.50 (t, 2H), 3.22 (s, 3H), 3.44 (t,2H), 3.52 (s, 2H), 5.41 (s, 2H), 7.00-7.04 (m, 2H), 7.28-7.45 (m, 7H),7.82 (d, 1H), 8.03 (s, 1H), 8.16 (d, 1H), 8.41 (s, 1H), 9.79 (s, 1H),11.51 (s, 1H), 11.99 (br s, 1H).

Example 80 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[6-oxo-5-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrilefollowed by preparative HPLC at pH 4 and isolated as a yellow solid, 3mg, 5%. LC/MS: RT=0.93 Min (270 nm), m/z=525 [M+H]. Total run time 1.9min (super short pos).

¹H NMR (d₆ DMSO): δ 1.4 (m, 2H), 1.50 (m, 5H), 2.40 (m, 3H), 3.45 (s,2H), 5.40 (s, 2H), 7.02 (br, 2H), 7.05 (m, 1H), 7.22 (t, 1H), 7.35 (m,2H), 7.45 (m, 2H), 7.80 (d, 1H), 8.05 (s, 1H), 8.16 (d, 1H), 8.40 (s,1H), 9.80 (s, 1H), 11.52 (s, 1H)

Example 81 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-fluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 20 mg, 37%.

LC/MS: RT=1.58 Min (270 nm), m/z=543 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.70 (m, 2H), 1.85 (m, 2H), 2.3 (m, 2H), 3.50 (s,2H), 4.65 (br d, 1H), 5.40 (s, 2H), 6.95 (br s, 1H), 7.00 (dd, 1H), 7.25(t, 2H), 7.40 (m, 4H), 7.85 (d, 1H), 8.05 (s, 1H), 8.15 (s, 1H), 8.40(s, 1H), 9.75 (s, 1H),

Example 82 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-methyl-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 49 mg, 48%.

LC/MS: RT=1.63 Min (270 nm), m/z=539 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.90 (d, 3H), 1.10 (m, 2H), 1.30 (m, 1H), 1.58 (d,2H), 1.85 (t, 2H), 2.80 (d, 2H), 3.40 (s, 2H), 5.4 (s, 2H), 6.90 (br,1H), 7.00 (dd, 1H), 7.22 (t, 2H), 7.38 (m, 4H), 7.84 (d, 1H), 8.05 (s,1H), 8.10 (s, 1H), 8.40 (s, 1H), 9.75 (s, 1H),

Example 83 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[5-(5-ethylaminomethyl-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrilefollowed by preparative HPLC at pH 4, to furnish the title compound as ayellow solid, 16 mg, 18%.

LC/MS: RT=0.92 Min (270 nm), m/z=440 [Fragment]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.05 (t, 3H), 2.65 (q, 2H), 3.88 (s, 2H), 5.4 (s,2H), 7.04 (d, 1H), 7.06 (dd, 1H), 7.22 (t, 2H), 7.38 (m, 2H), 7.55 (dd,1H), 7.58 (s, 1H), 7.80 (s, 1H), 8.05 (s, 1H), 8.25 (d, 1H), 8.35 (s,1H), 8.44 (s, 1H) 9.85 (s, 1H), 11.6 (s, 1H).

Example 84 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(cyclohexyl-methyl-amino)-methyl]-1H-indol-2-yl}-6-oxo-1,6-dihydropyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrilefollowed by preparative HPLC at pH9, to furnish the title compound as ayellow solid, 12 mg, 15%.

LC/MS: RT=1.68 Min (270 nm), m/z=553 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.0-1.2 (m, 4H), 1.2-1.4 (m, 2H), 1.6 (d, 1H),1.66-1.84 (m, 4H), 2.28 (s, 3H), 3.62, (s, 2H), 5.4 (s, 2H), 7.02 (d,1H), 7.04-7.08 (dd, 1H), 7.24 (t, 2H), 7.34-7.40 (m, 2H), 7.42-7.46 (m,2H), 7.8 (d, 1H), 8.02 (s, 1H), 8.18 (s, 1H), 8.20 (s, 1H), 9.56 (s,1H), 11.5 (s, 1H).

Example 85 1-(1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid[6-oxo-5-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 37 mg, 54%.

LC/MS: RT=0.95 Min (270 nm), m/z=521 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.32-1.42 (m, 2H), 1.43-1.52 (m, 4H), 1.83-1.84 (d,3H), 2.25-2.36 (m, 4H), 3.45 (s, 2H), 5.67-5.72 (q, 1H), 7.01-7.44 (m,9H), 7.82-7.83 (d, 1H), 8.03 (s, 1H), 8.16-8.17 (d, 1H), 8.45 (s, 1H),9.78 (s, 1H), 11.51 (s, 1H), 11.92-12.03 (br s, 1H).

Example 86 1-(1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid[5-(5-morpholin-4-ylmethyl-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 15 mg, 23%.

LC/MS: RT=0.89 Min (270 nm), m/z=523 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.83-1.85 (d, 3H), 2.35 (m, 4H), 3.49 (s, 2H),3.55-3.57 (m, 4H), 5.67-5.74 (q, 1H), 6.99-7.46 (m, 9H), 7.82-7.83 (d,1H), 8.04 (s, 1H), 8.16-8.17 (d, 1H), 8.45 (s, 1H), 9.78 (s, 1H), 11.53(s, 1H), 11.90-12.05 (br s, 1H).

Example 87 1-(1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-fluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 16 mg, 46%.

LC/MS: RT=0.93 Min (270 nm), m/z=539 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.66-1.76 (m, 2H), 1.83-1.85 (m, 5H), 2.23-2.32 (m,2H), 3.50 (s, 2H), 4.60-4.70 (d, 1H), 5.67-5.72 (q, 1H), 7.0-7.05 (m,2H), 7.26-7.45 (m, 7H), 7.82-7.83 (d, 1H), 8.04 (s, 1H), 8.16-8.17 (d,1H), 8.45 (s, 1H), 9.78 (s, 1H), 11.53 (s, 1H), 11.95-12.00 (br s, 1H).

Example 88 1-[1-(4-Fluoro-phenyl)-ethyl]-1H-pyrazole-4-carboxylic acid[6-oxo-5-(5-piperidin-1-ylmethyl-1-H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 3 mg, 9%.

LC/MS: RT=0.95 Min (254 nm), m/z=539 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.36-1.40 (br s, 2H), 1.43-1.50 (br m, 4H), 1.82 (d,3H), 2.26-2.32 (br m, 4H), 3.44 (s, 2H), 5.70 (q, 1H), 7.00 (m, 2H),7.20 (m, 2H), 7.32-7.44 (m, 4H), 7.82 (d, 1H), 8.02 (s, 1H), 8.18 (d,1H), 8.44 (s, 1H), 9.80 (s, 1H), 11.52 (s, 1H), 12.00 (br s, 1H)

Example 89 1-[1-(4-Fluoro-phenyl)-ethyl]-1H-pyrazole-4-carboxylic acid{5-[5-(4-methylpiperazin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 9 mg, 30%.

LC/MS: RT=0.89 Min (254 nm), m/z=554 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.80 (d, 3H), 2.15 (s, 3H), 2.2-2.4 (br m, 8H), 3.42(s, 2H), 5.70 (q, 1H), 7.00 (m, 2H), 7.18-7.22 (m, 2H), 7.36-7.40 (m,2H), 7.4-7.48 (m, 2H), 7.82 (d, 1H), 8.04 (s, 1H), 8.16 (d, 1H), 8.44(s, 1H), 9.78 (s, 1H), 11.52 (s, 1H), 12.00 (br s, 1H).

Example 90 1-[1-(Fluoro-phenyl)-ethyl]-1H-pyrrazole-4-carboxylic acid{5-[5-(4-fluoro-piperidin-1ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 2 mg, 14%.

LC/MS: RT=0.95 Min (254 nm), m/z=557 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.60-1.73 (m, 2H), 1.73-1.90 (m, 2H), 1.81 (d, 3H),2.20-2.30 (m, 2H), 2.43-2.55 (m, 2H obscured by DMSO peak), 3.50 (s,2H), 4.56-4.76 (m, 1H), 5.70 (q, 1H), 7.00 (m, 2H), 7.20 (m, 2H),7.32-7.38 (m, 2H), 7.4-7.46 (m, 2H), 7.82 (d, 1H), 8.04 (s, 1H), 8.16(d, 1H), 8.44 (s, 1H), 9.78 (s, 1H), 11.52 (s, 1H), 11.98 (br s, 1H)

Example 91 1-(1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid{5-[5-(cis-2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 34 mg, 31%.

LC/MS: RT=1.61 Min (270 nm), m/z=550 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.0 (d, 6H), 1.62 (t, 2H), 1.82 (d, 3H), 2.68 (m,2H), 3.48 (s, 2H), 3.55 (m, 2H), 5.7 (q, 1H), 7.0 (m, 2H), 7.20-7.42 (m,7H), 7.80 (d, 1H), 8.05 (s, 1H), 8.10 (s, 1H), 8.42 (s, 1H), 9.78 (s,1H),

Example 92 1-(1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-methyl-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51. The titlecompound was purified by trituration with acetonitrile, and isolated asa yellow solid, 57 mg, 49%.

LC/MS: RT=1.66 Min (270 nm), m/z=535 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.87 (d, 3H), 1.12 (m, 2H), 1.30 (m, 1H), 1.54 (m,2H), 1.84 (d, 3H), 1.87 (m, 2H), 2.78 (m, 2H), 3.46 (s, 2H), 5.70 (q,1H), 7.00-7.03 (m, 2H), 7.28-7.44 (m, 7H), 7.82 (d, 1H), 8.04 (s, 1H),8.15 (d, 1H), 8.45 (s, 1H), 9.78 (s, 1H), 11.51 (s, 1H), 11.99 (br s,1H).

Example 93 1-(1-Phenylethyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydropyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6,following the same experimental procedures as for Example 20, exceptthat the relevant carboxylic acid,1-(1-phenyl-ethyl)-1H-pyrazole-4-carboxylic acid, was converted to1-(1-phenyl-ethyl)-1H-pyrazole-4-carbonyl chloride and then coupled tothe amine using the same experimental described for Example 51.

The title compound was purified by flash chromatography on SiO₂ withethyl acetate and isolated as a yellow solid, 57 mg, 49%.

LC/MS: RT=2.03 Min (270 nm), m/z=424 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.85 (d, 3H), 5.70 (q, 1H), 6.95 (t, 1H), 7.10 (m,2H), 7.30 (m, 3H), 7.35 (m, 2H), 7.55 (m, 2H), 7.80 (d, 1H), 8.05 (s,1H), 8.20 (d, 1H), 8.45 (s, 1H), 9.75 (s, 1H), 11.54 (br s, 1H), 11.99(br s, 1H).

Example 94 1-(3-Phenyl-propyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6,following the same experimental procedures as for Example 20, exceptthat the relevant carboxylic acid,1-(3-Phenyl-propyl)-1H-pyrazole-4-carboxylic acid, was converted to1-(3-Phenyl-propyl)-1H-pyrazole-4-carbonyl chloride, and then coupled tothe amine using the same experimental described for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 30 mg, 48%.

LC/MS: RT=2.22 Min (270 nm), m/z=436 [M−H]. Total run time 3.75 min(short pos/neg).

¹H NMR (d₆ DMSO): δ 2.12 (t, 2H), 2.55 (m, 2H), 4.17 (t, 2H), 6.97 (m,1H), 7.07 (m, 2H) 7.22 (m, 3H), 7.30 (m, 2H), 7.52 (t, 2H), 7.82 (s,1H), 8.03 (s, 1H), 8.20 (s, 1H), 8.35 (s, 1H), 9.77 (br s, 1H), 11.57(br s, 1H), 12.0 (br s, 1H)

Example 95 1-[2-(4-Fluoro-phenyl)-ethyl]-1H-pyrazole-4-carboxylic acid[6-oxo-5-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with diethyl ether, andisolated as a yellow solid, 30 mg, 42%.

LC/MS: RT=0.94 Min (270 nm), m/z=539 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.34-1.42 (m, 2H), 1.46-1.52 (m, 4H), 2.30-2.37 (m,4H), 3.11-3.16 (m, 2H), 3.45 (s, 2H), 4.38-4.42 (t, 2H), 6.97-7.21 (m,6H), 7.40-7.43 (m, 2H), 7.82-7.83 (d, 1H), 8.03 (s, 1H), 8.17-8.18 (d,1H), 8.19 (s, 1H), 9.76 (s, 1H), 11.58 (s, 1H), 11.95-12.00 (br s, 1H).

Example 96 1-[2-(4-Fluoro-phenyl)-ethyl]-1H-pyrazole-4-carboxylic acid{5-[5-(4-fluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51. The titlecompound was purified by trituration with diethyl ether, and isolated asa yellow solid, 36 mg, 51%.

LC/MS: RT=0.94 Min (270 nm), m/z=557 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.69-1.92 (m, 4H), 2.24-2.33 (m, 2H), 3.11-3.18 (m,4H), 3.50 (s, 2H), 4.38-4.42 (t, 2H), 4.59-4.75 (m, 1H), 7.00-7.21 (m,6H), 7.41-7.44 (m, 2H), 7.83-7.84 (d, 1H), 8.03 (s, 1H), 8.19-8.20 (m,2H), 9.78 (s, 1H), 11.62-11.69 (br s, 1H).

Example 975-[5-(4-Fluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid [1-(3,4-difluoro-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 9, usingintermediate (8b) and applying the same the experimental procedures asfor Example 1. The title compound was purified by trituration withacetonitrile followed by preparative HPLC at pH 4 and isolated as ayellow solid, 24 mg, 14%.

LC/MS: RT=0.95 Min (270 nm), m/z=561 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.75 (br m, 2H), 1.85 (br m, 2H), 2.30 (br m, 2H),2.55 (br m, 2H), 3.53 (s, 2H), 4.65 (m, 1H), 5.35 (s, 2H), 7.05 (dd,1H), 7.15 (m, 1H), 7.25 (d, 1H), 7.30 (m, 1H), 7.45 (m, 3H), 7.55 (d,1H), 8.10 (d, 1H), 8.15 (s, 1H), 8.25 (s, 1H), 8.55 (d, 1H), 10.40 (s,1H), 11.48 (br s, 1H).

Example 986-oxo-5-(5-pyrrolidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridine-3-carboxylicacid [1-(3,4-difluoro-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 9, usingintermediate (8b) and applying the same the experimental procedures asfor Example 1. The title compound was purified by trituration withacetonitrile followed by preparative HPLC at pH 4 and isolated as ayellow solid, 12 mg, 8%.

LC/MS: RT=0.95 Min (270 nm), m/z=529 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.75 (br s, 4H), 2.60 (s, 4H), 3.75 (s, 2H), 5.30(s, 2H), 7.10 (m, 2H), 7.20 (d, 1H), 7.45 (m, 3H), 7.65 (d, 1H), 8.10(d, 1H), 8.15 (s, 1H), 8.25 (br s, 1H), 8.55 (d, 1H), 10.40 (s, 1H),11.51 (br s, 1H).

Example 995-(5-Morpholin-4-ylmethyl-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid [1-(3,4-difluoro-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 9, usingintermediate (8b) and applying the same the experimental procedures asfor Example 1. The title compound was purified by trituration withacetonitrile, and isolated as a yellow solid, 65 mg, 27%.

LC/MS: RT=1.70 Min (270 nm), m/z=545 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.40 (br s, 4H), 3.50 (s, 2H), 3.60 (t, 4H), 5.30(s, 2H), 7.10 (m, 2H), 7.20 (d, 1H), 7.35 (m, 1H), 7.45 (m, 3H), 7.65(d, 1H), 8.15 (d, 1H), 8.20 (d, 1H), 8.65 (d, 1H), 10.35 (s, 1H), 11.46(br s, 1H), 12.44 (br s, 1H).

Example 1005-[5-(4-Hydroxypiperidin-1-ylmethyl)-1H-indol-2yl]-6-oxo-1,6-dihydropyridine-3-carboxylicacid[1-(3,4-difluorobenzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 9, usingintermediate (8b) and applying the same the experimental procedures asfor Example 1. The crude product was purified by preparative HPLC at pH4 and isolated as a yellow solid, 15 mg (7%)

LC/MS: RT=0.91 Min (270 nm); m/z=559 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.45 (m, 2H), 1.85 (m, 2H), 2.25 (m, 2H), 2.85 (m,2H), 3.55 (m, 1H), 3.75 (s, 2H), 5.40 (s, 2H), 7.10 (m, 2H), 7.25 (d,1H), 7.35 (m, 1H), 7.45 (m, 3H), 7.65 (d, 1H), 8.15 (d, 1H), 8.20 (d,1H), 8.35 (br s, 1H), 8.65 (d, 1H), 10.45 (s, 1H), 11.52 (br s, 1H).

Example 1015-(5-{[(2-hydroxyethyl)-methylamino]-methyl}-1H-indol-2yl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid[1-(3,4-difluorobenzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 9, usingintermediate (8b) and applying the same the experimental procedures asfor Example 1. The crude product was purified by preparative HPLC at pH4 to give the product as a yellow solid, 21 mg, 11%.

LC/MS: RT=0.91 Min (270 nm), m/z=533 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 2.25 (s, 3H), 2.45 (t, 2H), 3.55 (t, 2H), 3.65 (s,2H), 5.35 (s, 2H), 7.10 (m, 2H), 7.25 (d, 1H), 7.35 (m, 1H), 7.45 (m,3H), 7.65 (d, 1H), 8.10 (d, 1H), 8.15 (d, 1H), 8.25 (br s, 1H), 8.60 (d,1H), 10.35 (s, 1H), 11.50 (br s, 1H).

Example 1025-(5-{[Ethyl-(2-hydroxyethyl)amino]-methyl}-1H-indol-2yl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid[1-(3,4-difluorobenzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 9, usingintermediate (8b) and applying the same the experimental procedures asfor Example 1. The crude product was purified by preparative HPLC at pH4 to give the product as a yellow solid, 18 mg, 9%.

LC/MS: RT=0.93 Min (270 nm), m/z=547.2 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.05 (t, 3H), 2.55 (t, 2H), 2.60 (t, 2H), 3.50 (t,2H), 3.69 (s, 2H), 5.35 (s, 2H), 7.10 (dd, 2H), 7.25 (d, 1H), 7.35 (m,1H), 7.45 (m, 3H), 7.65 (d, 1H), 8.10 (d, 1H), 8.15 (d, 1H), 8.25 (br s,1H), 8.60 (d, 1H), 10.35 (s, 1H), 11.50 (br s, 1H).

Example 1035-{5-[(2-Hydroxyethylamino)-methyl]-1H-indol-2yl}-6-oxo-1,6-dihydropyridine-3-carboxylicacid[1-(3,4-difluorobenzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 9, usingintermediate (8b) and applying the same the experimental procedures asfor Example 1. The crude product was purified by preparative HPLC at pH4 to give the product as a yellow solid, 12 mg, 6%.

LC/MS: RT=0.91 Min (270 nm), m/z=458 [Fragment]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 2.75 (t, 2H), 3.55 (t, 2H), 3.93 (s, 2H), 5.35 (s,2H), 7.10 (m, 1H), 7.15 (d, 1H), 7.25 (m, 1H), 7.35 (m, 1H), 7.45 (m,2H), 7.55 (s, 1H), 7.65 (d, 1H), 8.10 (d, 1H), 8.15 (d, 1H), 8.20 (s,1H), 8.30 (br s, 1H), 8.60 (d, 1H), 10.40 (s, 1H), 11.58 (br s, 1H).

Example 1045-[5-(4-Methyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid [1-(3,4-difluoro-benzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 9, usingintermediate (8b) and applying the same the experimental procedures asfor Example 1. The crude product was purified by preparative HPLC at pH4 to give the product as a yellow solid, 10 mg, 5%.

LC/MS: RT=0.92 Min (270 nm), m/z=558 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 2.35 (s, 3H), 2.55 (br s, 6H), 3.95 (br s, 4H), 5.50(s, 2H), 7.20 (dd, 1H), 7.25 (m, 1H), 7.40 (d, 1H), 7.50 (m, 1H), 7.60(m, 3H), 7.80 (s, 1H), 8.25 (d, 1H), 8.30 (d, 1H), 8.75 (d, 1H), 10.50(s, 1H), 11.50 (br s, 1H).

Example 1055-{5-[4-(2-Hydroxyethyl)-piperazin-1-ylmethyl]-1H-indol-2yl}-6-oxo-1,6-dihydropyridine-3-carboxylicacid[1-(3,4-difluorobenzyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 9, usingintermediate (8b) and applying the same the experimental procedures asfor Example 1. The crude product was purified by preparative HPLC at pH4 to give the product as a yellow solid, 8 mg, 3%.

LC/MS: RT=0.91 Min (270 nm), m/z=588 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 2.40 (m, 10H), 3.45 (m, 4H), 5.35 (s, 2H), 7.04 (dd,1H), 7.10 (m, 1H), 7.21 (d, 1H), 7.33 (m, 1H), 7.42 (m, 3H), 7.63 (s,1H), 8.15 (d, 1H), 8.20 (s, 1H), 8.25 (br s, 1H), 8.60 (d, 1H), 10.40(s, 1H), 11.50 (br s, 1H).

Example 106 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-dimethylaminomethyl-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51, except(1H-Indol-4-yl)-methanol was used.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 13 mg, 33%.

LC/MS RT=0.88 Min (270 nm), m/z=467 [M+H]. Total run time 1.9 min (supershort pos/neg).

¹H NMR (d₆ DMSO): δ 2.19 (s, 3H), 2.49 (s, 3H), 3.64 (s, 2H), 5.40 (s,2H), 6.89 (d, 1h), 7.01 (t, 1H), 7.14 (br d, 1h), 7.38 (m, 6H), 7.88 (brs, 1H), 8.03 (s, 1H), 8.20 (d, 1H), 8.41 (s, 1H), 9.89 (s, 1H), 11.60(s, 1H)

Example 107 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[4-(4-methyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51, except(1H-Indol-4-yl)-methanol was used.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 17 mg, 26%.

LC/MS RT=0.89 Min (270 nm), m/z=522 [M+H]. Total run time 1.9 min (supershort pos/neg).

¹H NMR (d₆ DMSO): δ 2.13 (s, 3H), 2.33 (br s, 4H), 2.41 (br s, 4H), 3.33(s, 2H), 4.29 (s, 2H), 6.91 (d, 1H), 7.02 (d, 1H), 7.14 (br s, 1H), 7.34(m, 6H), 7.85 (br s, 1H), 8.03 (s, 1H), 8.19 (d, 1H), 8.41 (s, 1H), 9.78(s, 1H), 11.56 (s, 1H), 12.00 (br s, 1H)

Example 108 1-Benzyl-1H-pyrazole-4-carboxylic acid[6-oxo-5-(4-piperidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51, except(1H-Indol-4-yl)-methanol was used. The final step, deprotection, wasachieved using the following alternative to the usual procedure.

2-[5-[(1-Benzyl-1H-pyrazole-4-carbonyl)-amino]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-4-piperidin-1-ylmethyl-indole-1-carboxylicacid tert-butyl ester (110 mg, 0.149 mmol) was stirred indichloromethane (5 mL) at −78° C. and then boron tribromide 1.0Msolution in dichloromethane (2 mL, 2 mmol) was added drop wise. Afteraddition the cooling was removed and the reaction was stirred at RT for1 hour. The reaction mixture was cooled to −78° C. and methanol (2 mL)was added. Again the cooling was removed and the reaction stirred at RT,followed by concentration in vacuo. The residue was partitioned betweenethyl acetate and water. The organics were separated, washed with sodiumhydrogen bicarbonate, dried (Na₂SO₄) and concentrated in vacuo tofurnish a dark yellow solid. This was purified by trituration with ethylacetate to give the title compound as a yellow solid, 31 mg, 41%.

LC/MS RT=1.55 Min (270 nm), m/z=507 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₄-MeOD): δ 1.57 (m, 2H), 1.73 (m, 4H) 2.92 (m, 4H), 4.17 (m,2H), 5.43 (s, 2H), 7.13 (d, 1H), 7.20 (m, 1H), 7.28 (s, 1H), 7.36 (m,5H), 7.48 (m, 1H), 7.88 (s, 1H), 8.08 (s, 1H), 8.29 (s, 1H), 8.34 (s,1H).

Example 109 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[4-(cis-2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51, except(1H-Indol-4-yl)-methanol was used and the alternative deprotectionmethod described for Example 108 was adopted.

The title compound was purified by trituration with ethyl acetate, andisolated as a yellow solid, 45 mg, 56%.

LC/MS RT=1.56 Min (270 nm), m/z=537 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₄-MeOD): δ 1.11 (d, 6H), 1.88 (t, 2H) 2.86 (d, 2H), 3.70 (m,2H), 3.83 (s, 2H), 5.42 (s, 2H), 7.03 (m, 1H), 7.13 (m, 1H), 7.25 (s,1H), 7.37 (m, 6H), 7.95 (d, 1H), 8.09 (s, 1H), 8.28 (m, 2H).

Example 110 5-(1H-Indol-2-yl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid [1-(6-fluoro-pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-amide

The title compound was prepared by the route outlined in Scheme 1,following the same experimental procedures as for Examples 1 and 2.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 4 mg, 8%.

LC/MS RT=1.12 Min (270 nm), m/z=429 [M+H]. Total run time 1.9 min (supershort pos/neg).

¹H NMR (d₆ DMSO): δ 5.38 (s, 2H), 7.00 (td, 1H), 7.09 (td, 1H), 7.19(dd, 1H), 7.24 (br d, 1H), 7.49 (br d, 1H), 7.55 (br d, 1H), 7.62 (s,1H), 7.87 (td, 1H), 8.11 (d, 1H), 8.19 (s, 1H), 8.21 (br s, 1H), 8.55(d, 1H), 10.31 (br s, 1H), 11.50 (br s, 1H).

Example 111 1-(6-Fluoro-pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylicacid [5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6,following the same experimental procedures as for Examples 20 and 21.

The crude product was purified by preparative HPLC at pH 4 to give theproduct as a yellow solid, 3 mg, 11%.

LC/MS RT=1.08 Min (270 nm), m/z=429 [M+H]. Total run time 1.9 min (supershort pos/neg).

¹H NMR (d₄-MeOD): δ 5.45 (s, 2H), 7.00 (t, 1H), 7.02 (s, 1H), 7.09 (m,2H), 7.41 (d, 1H), 7.53 (d, 1H), 7.92 (m, 2H), 8.07 (s, 1H), 8.21 (m,2H), 8.33 (s, 1H).

Example 112 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-methyl-piperazin-1-yl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared according to the route outlined inScheme 10.

Step 1: Preparation of 1-Methyl-4-(3-methyl-4-nitro-phenyl)-piperazine(10a)

A mixture of 5-fluoro-2-nitrotoluene (2.5 g, 16 mmol),N-methylpiperazine (2 mL, 18 mmol) and potassium carbonate (2.7 g, 19mmol) in DMSO (7 mL) was stirred and heated at 100° C. for 2 hours. Thereaction mixture was cooled to ambient temperature and then diluted withethyl acetate (100 mL), washed with water (3×30 mL), brine, dried(MgSO₄) and concentrated in vacuo. The resultant crude product waspurified by flash chromatography on SiO₂ eluting withdichloromethane—40% methanol/dichloromethane (gradient) to afford thedesired title compound as a yellow solid, 3.67 g, 97%.

Step 2: Preparation of 5-(4-Methyl-piperazin-1-yl)-1H-indole (10b)

A solution of 1-methyl-4-(3-methyl-4-nitro-phenyl)-piperazine (10a),(2.63 g, 11.2 mmol), N,N-dimethylformamide dimethyl acetal (4.7 mL,35.84 mmol) and pyrrolidine (1.5 mL, 17.9 mmol) in anhydrousN,N-dimethylformamide (20 mL) was heated at 120° C. for 18 hours. Thereaction mixture was concentrated in vacuo, taken up in ethanol (50 mL)containing 2 mL of water and to this was added ammonium formate (3.67 g,58.2 mmol). Palladium, 10 wt. % on activated carbon (0.84 g) was addedand the suspension was stirred and heated at 50° C. for 30 minutes. Thereaction mixture was then filtered through a celite pad and the padrinsed with hot methanol (20 mL). The combined filtrate and washingswere concentrated in vacuo and the residue was taken up in ethyl acetate(100 mL), washed with aqueous saturated sodium bicarbonate solution(2×100 mL), brine, dried (MgSO₄) and concentrated in vacuo. Theresultant crude product was purified by flash chromatography on SiO₂eluting first with hexane and then 15% ethyl acetate/hexane to affordthe desired title compound as an off-white solid, 1.44 g, 60%.

Step 3: Preparation of 5-(4-Methyl-piperazin-1-yl)-indole-1-carboxylicacid tert-butyl ester (10c)

A solution of 5-(4-methyl-piperazin-1-yl)-1H-indole (10b), (1.67 g, 7.7mmol) in dichloromethane (40 mL) was added di-tert-butyl dicarbonate(1.87 g, 8.6 mmol) drop wise at ambient temperature as a solution indichloromethane (5 mL). 4-Dimethylaminopyridine (0.095 g, 0.8 mmol) wasadded and the reaction stirred at ambient temperature for 18 hours. Thereaction mixture was washed with aqueous saturated sodium bicarbonatesolution (100 mL), brine, dried (MgSO₄) and concentrated in vacuo. Theresultant crude product was purified by flash chromatography on SiO₂eluting with dichloromethane—15% methanol/dichloromethane (gradient) toafford the desired title compound as a yellow solid, 2.33 g, 95%.

Step 4: Preparation of5-(4-Methyl-piperazin-1-yl)-2-[5-nitro-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (10d)

The title compound was prepared by the route outlined in Scheme 10 andusing the experimental from Example 37, Step 3, with intermediate (10c),5-(4-methyl-piperazin-1-yl)-indole-1-carboxylic acid tert-butyl ester(2.33 g, 7.4 mmol) and3-iodo-5-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyridin-2-one(2.66 g, 6.7 mmol) which had been synthesised according to the protocoldescribed for intermediate (6a) in example 20. The resultant solid waspurified via trituration using diethyl ether, to afford the titlecompound as a pale brown solid, 1.73 g, 40%.

Step 5: Preparation of2-[5-Amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-methyl-piperazin-1-yl)-indole-1-carboxylicacid tert-butyl ester (10e)

The title compound was prepared by the route outlined in Scheme 10 andusing the experimental from Example 20, Step 3, with intermediate (10d),5-(4-methyl-piperazin-1-yl)-2-[5-nitro-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (0.73 g, 1.2 mmol). The resultant crude productwas purified by flash chromatography on SiO₂ eluting withdichloromethane—20% methanol/dichloromethane (gradient) to afford thedesired title compound as a dark yellow foam, 0.435 g, 63%.

Step 6: preparation of2-[5-{[1-(4-Methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-methyl-piperazin-1-yl)-indole-1-carboxylicacid tert-butyl ester (10f)

The title compound was prepared by the route outlined in Scheme 10 andusing the experimental from Example 115, Step 4, with intermediate(10e),2-[5-amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-methyl-piperazin-1-yl)-indole-1-carboxylicacid tert-butyl ester (0.1 g, 0.18 mmol) and1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl chloride (0.047 g, 0.2 mmol).The resultant crude product was purified by flash chromatography on SiO₂eluting with dichloromethane—8% methanol/dichloromethane (gradient) toafford the desired title compound as a pale brown solid, 0.107 g, 79%.

Step 7: Preparation of the Title Compound:1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-methyl-piperazin-1-yl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 10,following the same experimental procedures as for Example 37. It waspurified by trituration with acetonitrile, and isolated as a yellowsolid, 43 mg, 59%.

LC/MS: RT=1.45 Min (270 nm), m/z=522 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.23 (s, 3H), 2.29 (s, 3H), 2.48 (m, 4H), 3.04 (m,4H), 5.34 (s, 2H), 6.86-6.89 (m, 2H), 6.97 (m, 1H), 7.19 (m, 4H), 7.37(d, 1H), 7.82 (d, 1H), 8.01 (s, 1H), 8.11 (d, 1H), 8.37 (s, 1H), 9.76(s, 1H), 11.37 (s, 1H), 11.96 (br s, 1H).

Example 113 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(4-methyl-piperazin-1-yl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 10,following the same experimental procedures as for Example 112. The titlecompound was purified by trituration with acetonitrile, and isolated asa yellow solid, 40 mg, 61%.

LC/MS: RT=1.49 Min (270 nm), m/z=508 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.23 (s, 3H), 2.48 (m, 4H), 3.05 (m, 4H), 5.40 (s,2H), 6.86-6.89 (m, 2H), 6.97 (m, 1H), 7.28-7.40 (m, 6H), 7.82 (d, 1H),8.03 (s, 1H), 8.12 (d, 1H), 8.41 (s, 1H), 9.78 (s, 1H), 11.36 (s, 1H),11.97 (br s, 1H).

Example 114 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-methyl-piperazin-1-yl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 10,following the same experimental procedures as for Example 112. The titlecompound was purified by trituration with acetonitrile, and isolated asa yellow solid, 38 mg, 57%.

LC/MS: RT=1.52 Min (270 nm), m/z=526 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.22 (s, 3H), 2.48 (m, 4H), 3.05 (m, 4H), 5.39 (s,2H), 6.86-6.89 (m, 2H), 6.97 (m, 1H), 7.19-7.24 (m, 2H), 7.34-7.39 (m,3H), 7.82 (d, 1H), 8.03 (s, 1H), 8.12 (d, 1H), 8.41 (s, 1H), 9.78 (s,1H), 11.36 (s, 1H), 11.97 (br s, 1H).

Example 115 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{6-oxo-5-[5-(2-piperidin-1-yl-ethoxy)-1H-indol-2-yl]-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared according to the route outlined inScheme 11.

Step 1: Preparation of5-(tert-Butyl-dimethyl-silanyloxy)-indole-1-carboxylic acid tert-butylester (11a)

The title compound was prepared by the route outlined in Scheme 11 andusing the experimental from Example 37, Step 2, with intermediate1H-Indol-5-ol (5.54 g, 7.4 mmol). The resultant crude product waspurified by flash chromatography on SiO₂ with hexane—10% ethylacetate/hexane (gradient) to afford the title compound as a white solid,13.41 g, 93%.

Step 2: Preparation of5-(tert-Butyl-dimethyl-silanyloxy)-2-[5-nitro-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (11b)

The title compound was prepared by the route outlined in Scheme 11 andusing the experimental from Example 37, Step 3, with intermediate5-(tert-butyl-dimethyl-silanyloxy)-indole-1-carboxylic acid tert-butylester (11a) (2.90 g, 8.3 mmol) and (6a),3-iodo-5-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyridin-2-one (3g, 7.6 mmol). The resultant crude product was purified by flashchromatography on SiO₂ with hexane—20% ethyl acetate/hexane (gradient)to afford after trituration using hexane, the title compound as a paleyellow solid, 3.67 g, 79%.

Step 3: Preparation of2-[5-Amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(tert-butyl-dimethyl-silanyloxy)-indole-1-carboxylicacid tert-butyl ester (11c)

The title compound was prepared by the route outlined in Scheme 11 andusing the experimental from Example 20, Step 3, with intermediate (11b)5-(tert-butyl-dimethyl-silanyloxy)-2-[5-nitro-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (3.65 g, 5.93 mmol). The resultant crude productwas purified by flash chromatography on SiO₂ with hexane—40% ethylacetate/hexane (gradient) to afford the title compound as a dark yellowfoam, 2.615 g, 75%.

Step 4: Preparation of5-(tert-Butyl-dimethyl-silanyloxy)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (11d)

Intermediate (11c),2-[5-amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(tert-butyl-dimethyl-silanyloxy)-indole-1-carboxylicacid tert-butyl ester (1.3 g, 2.2 mmol) was stirred in dichloromethane(50 mL) at RT with triethylamine (444 mg, 0.612 mL, 4.4 mmol). Thereaction mixture was cooled to 5° C. and then a solution of1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl chloride (2.86 mmol, 0.67 g),which had been prepared according to the protocol below, indichloromethane (10 ml), was added drop wise. After addition thereaction was stirred at RT for 3 hrs and then the reaction mixture waswashed with saturated sodium hydrogen carbonate solution (2×50 mL),brine (50 ml), dried (Na₂SO₄) and concentrated in vacuo. The resultantcrude product was purified by flash chromatography on SiO₂ eluting withhexane—50% ethyl acetate/hexane (gradient) and further purified viatrituration with isohexane (20 mL) and diethyl ether (20 mL). The solidswere separated by filtration and dried in vacuo to afford the desiredintermediate as a white solid, 1.56 g, 90%.

Preparation of 1-(4-Methyl-benzyl)-1H-pyrazole-4-carbonyl chloride usedin Step 4, above.

1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid (0.618 g, 2.86 mmol),which had been prepared according to the protocol described forintermediate (6e), in Example 21, was stirred in toluene (20 mL) at RTand thionyl chloride (681 mg, 0.42 mL, 5.72 mmol) was added. Thereaction mixture was slowly heated to 90° C. and heating continued for 3hrs. After cooling the reaction was concentrated in vacuo. Toluene wasadded to the residue and concentrated in vacuo. This was repeated afurther three times and the crude solid obtained was triturated usingisohexane. The solids were separated by filtration washed with isohexaneand dried in vacuo to afford 1-(4-methyl-benzyl)-1H-pyrazole-4-carbonylchloride as a white solid, 0.67 g, quant.

Step 5: Preparation of5-Hydroxy-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (11e)

Intermediate (11d),5-(tert-butyl-dimethyl-silanyloxy)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (1.55 g, 1.97 mmol) was stirred in tetrahydrofuran(40 mL) and cooled to 0° C. Tetrabutylammonium fluoride solution 1.0M intetrahydrofuran (2.08 mL, 2.08 mmol) was added drop wise at 0° C., andthen the reaction was allowed to attain ambient temperature, where itwas stirred for a further 2 hours. The reaction mixture was diluted withethyl acetate (30 mL), washed with water (30 mL), aqueous 0.5Nhydrochloric acid solution (30 mL), brine, dried (Na₂SO₄) andconcentrated in vacuo. The resultant green foam was purified viatrituration using diethyl ether, to afford the title compound as a paleyellow solid, 0.946 g, 71%.

Step 6: Preparation of2-[5-{[1-(4-Methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(2-piperidin-1-yl-ethoxy)-indole-1-carboxylicacid tert-butyl ester (11f)

To a solution of intermediate (11e),5-hydroxy-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (150 mg, 0.22 mmol) in N,N-dimethylformamide (3mL) was added 1-(2-chloroethyl)-piperidine hydrochloride (62 mg, 0.33mmol) and cesium carbonate (219 mg, 0.67 mmol). The reaction mixture washeated at 50° C. for 5 hours, and cooled to ambient temperature. Thereaction mixture was cooled and partitioned between ethyl acetate andwater. The ethyl acetate layer was separated and washed with brine,dried (Na₂SO₄) and concentrated in vacuo. The title compound waspurified by flash chromatography on SiO₂ eluting with dichloromethane—5%methanol/dichloromethane (gradient) to afford the desired title compoundas a pale yellow solid, 94 mg, 54%.

Step 7: Preparation of the Title Compound:1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{6-oxo-5-[5-(2-piperidin-1-yl-ethoxy)-1H-indol-2-yl]-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared according to the experimental used inExample 37, Step 8 with intermediate (11f),2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(2-piperidin-1-yl-ethoxy)-indole-1-carboxylicacid tert-butyl ester. Purification of the crude product wasaccomplished using trituration with acetonitrile. The title compound wasisolated as a yellow solid, 41 mg, 62%.

LC/MS: RT=1.76 Min (270 nm), m/z=551 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.38 (m, 2H), 1.50 (m, 4H), 2.29 (s, 3H), 2.44 (m,4H), 2.65 (t, 2H), 4.04 (t, 2H), 5.34 (s, 2H), 6.71 (dd, 1H), 6.92 (m,1H), 7.03 (d, 1H), 7.19 (m, 4H), 7.39 (d, 1H), 7.82 (d, 1H), 8.01 (s,1H), 8.14 (d, 1H), 8.37 (s, 1H), 9.76 (s, 1H), 11.46 (s, 1H), 11.97 (brs, 1H).

Example 116 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid(5-{5-[2-(3-fluoro-piperidin-1-yl)-ethoxy]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 21 mg, 75%.

LC/MS: RT=1.74 Min (270 nm), m/z=569 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.42-1.56 (m, 2H), 1.67-1.88 (m, 2H), 2.29 (s, 3H),2.33-2.57 (m, 3H), 2.75 (d, 2H), 2.86 (m, 1H), 4.06 (t, 2H), 4.63 (m,1H), 5.34 (s, 2H), 6.71 (dd, 1H), 6.93 (m, 1H), 7.04 (d, 1H), 7.19 (m,4H), 7.40 (d, 1H), 7.82 (d, 1H), 8.01 (s, 1H), 8.14 (d, 1H), 8.37 (s,1H), 9.76 (s, 1H), 11.45 (s, 1H), 11.98 (br s, 1H).

Example 117 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(3-morpholin-4-yl-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 51 mg, 71%.

LC/MS: RT=1.72 Min (270 nm), m/z=567 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.88 (m, 2H), 2.29 (s, 3H), 2.37 (m, 4H), 2.44 (d,2H), 3.58 (m, 4H), 3.99 (t, 2H), 5.34 (s, 2H), 6.71 (dd, 1H), 6.93 (m,1H), 7.01 (d, 1H), 7.19 (m, 4H), 7.40 (d, 1H), 7.82 (d, 1H), 8.01 (s,1H), 8.14 (d, 1H), 8.37 (s, 1H), 9.77 (s, 1H), 11.44 (s, 1H), 11.98 (brs, 1H).

Example 118 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 20 mg, 63%.

LC/MS: RT=1.71 Min (270 nm), m/z=553 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.29 (s, 3H), 2.50 (m, 4H), 2.70 (d, 2H), 3.59 (m,4H), 4.07 (t, 2H), 5.34 (s, 2H), 6.72 (dd, 1H), 6.93 (m, 1H), 7.04 (d,1H), 7.19 (m, 4H), 7.40 (d, 1H), 7.82 (d, 1H), 8.01 (s, 1H), 8.14 (d,1H), 8.37 (s, 1H), 9.76 (s, 1H), 11.45 (s, 1H), 11.96 (br s, 1H).

Example 119 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{6-oxo-5-[5-(3-piperidin-1-yl-propoxy)-1H-indol-2-yl]-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 47 mg, 87%.

LC/MS: RT=1.78 Min (270 nm), m/z=565 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.38 (m, 2H), 1.49 (m, 4H), 1.86 (m, 2H), 2.29 (s,3H), 2.33 (m, 4H), 2.39 (t, 2H), 3.97 (t, 2H), 5.34 (s, 2H), 6.70 (dd,1H), 6.92 (m, 1H), 7.01 (d, 1H), 7.19 (m, 4H), 7.39 (d, 1H), 7.82 (d,1H), 8.01 (s, 1H), 8.13 (d, 1H), 8.37 (s, 1H), 9.77 (s, 1H), 11.45 (s,1H), 11.98 (br s, 1H).

Example 120 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(3-dimethylamino-2,2-dimethyl-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 65 mg, 39%.

LC/MS: RT=1.58 Min (270 nm), m/z=539 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.96 (s, 6H), 2.21 (s, 6H), 2.24 (s, 2H), 3.67 (s,2H), 5.41 (s, 2H), 6.72 (dd, 1H), 6.92 (d, 1H), 7.01 (d, 1H), 7.28-7.40(m, 6H), 7.84 (d, 1H), 8.03 (s, 1H), 8.14 (d, 1H), 8.41 (s, 1H), 9.79(s, 1H), 11.43 (s, 1H), 11.99 (br s, 1H).

Example 121 1-(4-Trifluoromethyl-benzyl)-1H-pyrazole-4-carboxylic acid{6-oxo-5-[5-(2-piperidin-1-yl-ethoxy)-1H-indol-2-yl]-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115, but withthe following modification to Step 6.

A 3-5 mL microwave vial was charged with5-hydroxy-2-[2-oxo-5-{[1-(4-trifluoromethyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (150 mg, 0.207 mmol), triphenyl phosphine (87 mg,0.33 mmol), tetrahydrofuran (3 mL), 1-(2-hydroxyethyl)piperidine (40 mg,41 μL 0.31 mmol) and diisopropyl azidocarboxylate (67 mg, 654, 0.33mmol). The reaction mixture was then heated to 140° C. in the microwavefor 30 mins. The crude reaction mixture was purified by flashchromatography on SiO₂, eluting dichloromethane—15%methanol/dichloromethane (gradient) to afford the title compound as ayellow solid, 87 mg, 50%.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 33 mg, 52%.

LC/MS: RT=1.69 Min (270 nm), m/z=605 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.38 (m, 2H), 1.50 (m, 4H), 2.44 (m, 4H), 2.66 (t,2H), 4.04 (t, 2H), 5.54 (s, 2H), 6.71 (dd, 1H), 6.92 (m, 1H), 7.03 (d,1H), 7.40 (d, 1H), 7.46 (m, 2H), 7.76 (m, 2H), 7.83 (d, 1H), 8.07 (s,1H), 8.15 (d, 1H), 8.47 (s, 1H), 9.81 (s, 1H), 11.44 (s, 1H), 11.99 (brs, 1H).

Example 122 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(3-dimethylamino-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 6 mg, 23%.

LC/MS: RT=0.92 Min (270 nm), m/z=525 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.81-1.88 (m, 2H), 2.15 (s, 6H), 2.29 (s, 3H),2.34-2.38 (m, 2H), 3.96-3.99 (t, 2H), 5.34 (s, 2H), 6.69-6.72 (dd, 1H),6.92 (s, 1H), 7.00-7.01 (d, 1H), 7.19 (s, 4H), 7.38-7.41 (d, 1H),7.82-7.83 (d, 1H), 8.01 (s, 1H), 8.14-8.15 (d, 1H), 8.37 (s, 1H), 9.77(s, 1H), 11.47 (s, 1H), 11.92-12.00 (br s, 1H).

Example 123 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(3-diethylamino-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a brown solid, 8 mg, 35%.

LC/MS: RT=1.63 Min (270 nm), m/z=553 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.93-0.97 (t, 6H), 1.79-1.83 (m, 2H), 2.29 (s, 3H),3.96-3.99 (t, 2H), 5.34 (s, 2H), 6.68-6.70 (d, 1H), 6.89 (s, 1H), 7.00(s, 1H), 7.19 (s, 4H), 7.37-7.39 (d, 1H), 7.84 (s, 1H), 8.02 (s, 1H),8.14 (s, 1H), 8.37 (s, 1H), 9.78 (s, 1H), 11.62-11.70 (br s, 1H).

Example 124 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid(5-{5-[3-(4-methyl-piperazin-1-yl)-propoxyl-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 13 mg, 29%.

LC/MS: RT=0.91 Min (270 nm), m/z=580 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.83-1.89 (m, 2H), 2.14 (s, 3H), 2.29 (s, 3H),2.41-2.44 (t, 2H), 2.31-2.44 (br m, 8H), 3.96-3.99 (t, 2H), 5.34 (s,2H), 6.69-6.72 (dd, 1H), 6.92 (s, 1H), 7.00-7.01 (d, 1H), 7.19 (s, 4H),7.38-7.40 (d, 1H), 7.82-7.83 (d, 1H), 8.01 (s, 1H), 8.13-8.14 (d, 1H),8.37 (s, 1H), 9.78 (s, 1H), 11.46 (s, 1H), 11.90-12.00 (br s, 1H).

Example 125 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(2-diethylamino-ethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115.

The title compound was purified by trituration with acetonitrile, andisolated as a brown solid, 28 mg, 44%.

LC/MS: RT=0.93 Min (270 nm), m/z=539 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 0.97-1.00 (t, 6H), 2.29 (s, 3H), 2.53-2.59 (q, 4H),2.76-2.79 (t, 2H), 3.98-4.01 (t, 2H), 5.34 (s, 2H), 6.69-6.72 (dd, 1H),6.93 (s, 1H), 7.02-7.03 (d, 1H), 7.19 (s, 4H), 7.39-7.41 (d, 1H),7.82-7.83 (d, 1H), 8.01 (s, 1H), 8.14-8.15 (d, 1H), 8.37 (s, 1H), 9.78(s, 1H), 11.45 (s, 1H).

Example 126 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid(5-{5-[2-(4-methyl-piperazin-1-yl)-ethoxy]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 2 mg, 23%.

LC/MS: RT=0.92 Min (270 nm), m/z=566 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 2.14 (s, 3H), 2.29 (s, 3H), 2.24-2.40 (br m, 8H),2.64-2.70 (m, 2H), 4.03-4.06 (t, 2H), 5.34 (s, 2H), 6.69-6.72 (dd, 1H),6.91 (s, 1H), 7.02-7.03 (d, 1H), 7.19 (s, 4H), 7.38-7.40 (d, 1H),7.82-7.83 (d, 1H), 8.02 (s, 1H), 8.13-8.14 (d, 1H), 8.37 (s, 1H), 9.77(s, 1H), 11.48-11.61 (br s, 1H).

Example 127 1-(3-Ethyl-benzyl)-1H-pyrazole-4-carboxylic acid(5-{5-[3-(4-methyl-piperazin-1-yl)-propoxy]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 7 mg, 24%.

LC/MS: RT=0.96 Min (270 nm), m/z=594 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.15-1.19 (t, 3H), 1.84-1.88 (m, 2H), 2.14 (s, 3H),2.30-2.46 (br m, 8H), 2.41-2.44 (t, 2H), 2.57-2.62 (q, 2H), 3.96-3.99(t, 2H), 5.37 (s, 2H), 6.69-6.72 (dd, 1H), 6.92 (s, 1H), 7.00-7.01 (d,1H), 7.07-7.09 (d, 1H), 7.15 (s, 1H), 7.18 (s, 1H), 7.27-7.31 (m, 1H),7.38-7.41 (d, 1H), 7.82-7.83 (d, 1H), 8.03 (s, 1H), 8.14-8.15 (d, 1H),8.40 (s, 1H), 9.79 (s, 1H), 11.48 (s, 1H), 11.90-12.00 (br m, 1H).

Example 128 1-(3-Ethyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(2-dimethylamino-ethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 16 mg, 39%.

LC/MS: RT=0.95 Min (270 nm), m/z=525 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.15-1.19 (t, 3H), 2.22 (s, 6H), 2.58-2.64 (m, 4H),4.01-4.04 (t, 2H), 5.37 (s, 2H), 6.69-6.72 (dd, 1H), 6.91 (s, 1H),7.02-7.03 (d, 1H), 7.07-7.09 (d, 1H), 7.15 (s, 1H), 7.18 (s, 1H),7.27-7.31 (t, 1H), 7.38-7.41 (d, 1H), 7.82-7.83 (d, 1H), 8.03 (s, 1H),8.14-8.15 (d, 1H), 8.40 (s, 1H), 9.78 (s, 1H), 11.50-11.61 (s, 1H),11.86-12.00 (br s, 1H).

Example 129 1-(3-Ethyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(3-dimethylamino-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 6 mg, 20%.

LC/MS: RT=0.97 Min (270 nm), m/z=539 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.15-1.19 (t, 3H), 1.85 (m, 2H), 2.15 (s, 6H),2.33-2.40 (m, 4H), 3.96-3.98 (t, 2H), 5.37 (s, 2H), 6.69-6.72 (d, 1H),6.91 (s, 1H), 7.01 (s, 1H), 7.07-7.09 (d, 1H), 7.15 (s, 1H), 7.18 (s,1H), 7.27-7.31 (t, 1H), 7.38-7.40 (d, 1H), 7.84 (s, 1H), 8.03 (s, 1H),8.15 (s, 1H), 8.41 (s, 1H), 9.78 (s, 1H), 11.50 (s, 1H).

Example 130 1-(3-Ethyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(2-diethylamino-ethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a brown solid, 2 mg, 3%.

LC/MS: RT=0.98 Min (270 nm), m/z=553 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 0.97-1.00 (t, 6H), 1.15-1.19 (t, 3H), 2.53-2.60 (m,6H), 2.76-2.79 (t, 2H), 3.98-4.01 (t, 2H), 5.37 (s, 2H), 6.69-6.72 (dd,1H), 6.92-6.41 (m, 7H), 7.83 (m, 1H), 8.03 (s, 1H), 8.14-8.15 (s, 1H),8.40 (s, 1H), 9.79 (s, 1H), 11.44 (s, 1H), 11.90-12.00 (br m, 1H).

Example 131 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid(5-{5-[2-(2,6-dimethyl-morpholin-4-yl)-ethoxy]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 2 mg, 5%.

LC/MS: RT=0.98 Min (270 nm), m/z=581 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.04 (d, 6H), 1.73 (t, 2H), 2.29 (s, 3H), 2.68 (m,2H), 2.84 (d, 2H), 3.52-3.61 (m, 2H), 4.06 (t, 2H), 5.34 (s, 2H), 6.71(dd, 1H), 6.92 (d, 1H), 7.03 (d, 1H), 7.19 (s, 4H), 7.40 (d, 1H), 7.82(d, 1H), 8.01 (s, 1H), 8.15 (d, 1H), 8.37 (s, 1H), 9.77 (s, 1H), 11.47(br s, 1H), 11.92 (br s, 1H)

Example 132 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(2-dimethylamino-ethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115.

The title compound was purified by preparative HPLC at pH9 and isolatedas a yellow solid, 2 mg, 3%.

LC/MS: RT=0.91 Min (270 nm), m/z=511 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 2.23 (s, 6H), 2.29 (s, 3H), 2.63 (t, 2H), 4.03 (t,2H), 5.34 (s, 2H), 6.72 (dd, 1H), 6.93 (d, 1H), 7.03 (d, 1H), 7.19 (s,4H), 7.40 (d, 1H), 7.83 (d, 1H), 8.02 (s, 1H), 8.15 (d, 1H), 8.37 (s,1H), 9.78 (s, 1H), 11.45 (br s, 1H), 11.98 (br s, 1H)

Example 133 1-(3-Ethyl-benzyl)-1H-pyrazole-4-carboxylic acid(5-{5-[2-(4-methyl-piperazin-1-yl)-ethoxy]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 12 mg, 20%.

LC/MS: RT=0.97 Min (270 nm), m/z=580 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.17 (t, 3H), 1.23 (m, 2H), 2.14 (s, 3H), 2.24-2.38(m, 4H), 2.59 (q, 2H), 2.68 (t, 2H), 4.05 (t, 2H), 5.37 (s, 2H), 6.71(dd, 1H), 6.92 (d, 1H), 7.03 (d, 1H), 7.08 (d, 1H), 7.14-7.19 (m, 2H),7.26-7.31 (m, 1H), 7.39 (d, 1H), 7.83 (d, 1H), 8.03 (s, 1H), 8.15 (d,1H), 8.4 (s, 1H), 9.78 (s, 1H), 11.47 (br s, 1H), 11.95 (br s, 1H)

Example 134 1-(3-Ethyl-benzyl)-1H-pyrazole-4-carboxylic acid{6-oxo-5-[5-(3-piperidin-1-yl-propoxy)-1H-indol-2-yl]-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 13 mg, 25%.

LC/MS: RT=1.02 Min (270 nm), m/z=579 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.17 (t, 3H), 1.33-1.41 (m, 2H), 1.46-1.52 (m, 4H),1.85 (quintet, 2H), 2.30-2.35 (m, 4H), 2.39 (t, 2H), 2.59 (q, 2H), 3.97(t, 2H), 5.37 (s, 2H), 6.71 (dd, 1H), 6.92 (d, 1H), 7.01 (d, 1H), 7.08(d, 1H), 7.14-7.20 (m, 2H), 7.26-7.31 (m, 1H), 7.4 (d, 1H), 7.82 (d,1H), 8.03 (s, 1H), 8.15 (d, 1H), 8.4 (s, 1H), 9.79 (s, 1H), 11.46 (br s,1H), 11.95 (br s, 1H)

Example 135 1-(3-Ethyl-benzyl)-1H-pyrazole-4-carboxylic acid{6-oxo-5-[5-(2-piperidin-1-yl-ethoxy)-1H-indol-2-yl]-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 13 mg, 23%.

LC/MS: RT=1.74 Min (270 nm), m/z=565 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.17 (t, 3H), 1.4 (m, 2H), 1.5 (m, 4H), 2.45 (m,4H), 2.6 (q, 2H), 2.65 (t, 2H), 4.04 (t, 2H), 5.37 (s, 2H), 6.71 (dd,1H), 6.92 (s, 1H), 7.03 (d, 1H), 7.07 (d, 1H), 7.15-7.2 (m, 2H),7.26-7.31 (m, 1H), 7.4 (d, 1H), 7.82 (d, 1H), 8.03 (s, 1H), 8.15 (d,1H), 8.4 (s, 1H), 9.78 (br s, 1H), 11.45 (br s, 1H), 11.98 (br s, 1H)

Example 136 1-(3-Ethyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(3-diethylamino-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by preparative HPLC at pH9 and isolatedas a yellow solid, 6 mg, 12%.

LC/MS: RT=1.01 Min (270 nm), m/z=567 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 0.96 (t, 6H), 1.17 (t, 3H), 1.83 (quintet, 2H),2.44-2.52 (multiplicity partially obscured by residual DMSO peak, 4H),2.54-2.62 (m, 4H), 3.98 (t, 2H), 5.37 (s, 2H), 6.71 (dd, 1H), 6.93 (d,1H), 7.01 (d, 1H), 7.08 (d, 1H), 7.14-7.19 (m, 2H), 7.29 (m, 1H), 7.40(d, 1H), 7.83 (d, 1H), 8.03 (s, 1H), 8.16 (d, 1H), 8.40 (s, 1H), 9.81(s, 1H), 11.45 (br s, 1H), 11.96 (br s, 1H)

Example 137 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(3-dimethylamino-2,2-dimethyl-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with diethyl ether, andisolated as a yellow solid, 4 mg, 7%.

LC/MS: RT=1.67 Min (270 nm), m/z=553 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.96 (s, 6H), 2.2 (s, 6H), 2.24 (s, 2H), 2.29 (s,3H), 3.67 (s, 2H), 5.34 (s, 2H), 6.72 (dd, 1H), 6.92 (d, 1H) 7.01 (d,1H), 7.19 (s, 4H), 7.39 (d, 1H), 7.84 (s, 1H), 8.01 (s, 1H), 8.13 (s,1H), 8.37 (s, 1H), 9.77 (br s, 1H), 11.43 (br s, 1H), 11.98 (br s, 1H)

Example 138 1-(3-Ethyl-benzyl)-1H-pyrazole-4-carboxylic acid(5-{5-[2-(2,6-dimethyl-morpholin-4-yl)-ethoxy]1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by preparative HPLC at pH 4 and isolatedas a brown solid, 5 mg, 19%.

LC/MS: RT=1.01 Min (270 nm), m/z=595 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.04 (d, 6H), 1.17 (t, 3H), 1.73 (t, 2H), 2.59 (q,2H), 2.68 (m, 2H), 2.84 (d, 2H), 3.52-3.60 (m, 2H), 4.06 (m, 2H), 5.37(s, 2H), 6.72 (dd, 1H), 6.92 (d, 1H), 7.03 (d, 1H), 7.08 (d, 1H),7.14-7.19 (m, 2H), 7.29 (m, 1H), 7.40 (d, 1H), 7.83 (d, 1H), 8.03 (s,1H), 8.17 (d, 1H), 8.40 (s, 1H), 9.80 (s, 1H), 11.45 (br s, 1H), 11.95(br s, 1H)

Example 139 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(3-diethylamino-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 7 mg, 16%.

LC/MS: RT=0.92 Min (254 nm), m/z=539 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 0.95 (t, 6H), 1.80 (quintet, 2H), 2.45 (q, 4H), 2.53(t, 2H), 3.98 (t, 2H), 5.40 (s, 2H), 6.68-6.72 (dd, 1H), 6.92 (d, 1H),7.02 (d, 1H), 7.26-7.41 (m, 6H), 7.83 (d, 1H), 8.04 (s, 1H), 8.14 (d,1H), 8.40 (s, 1H), 9.77 (s, 1H), 11.44 (s, 1H), 11.98 (br s, 1H)

Example 140 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-[3-(4-methyl-piperazin-1-yl)-propoxy]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 17 mg, 36%.

LC/MS: RT=0.88 Min (254 nm), m/z=566 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.85 (quintet, 2H), 2.14 (s, 3H), 2.20-2.50 (br m,8H), 2.42 (t, 2H), 3.98 (t, 2H), 5.4 (s, 2H), 6.68-6.72 (dd, 1H), 6.91(d, 1H), 7 (d, 1H), 7.27-7.42 (m, 6H), 7.82 (d, 1H), 8.03 (s, 1H), 8.14(d, 1H), 8.40 (s, 1H), 9.78 (s, 1H), 11.45 (s, 1H), 11.98 (br s, 1H).

Example 141 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(2-diethylamino-ethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 14 mg, 32%.

LC/MS: RT=1.59 Min (254 nm), m/z=525 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.98 (t, 6H), 2.56 (q, 4H), 2.77 (t, 2H), 4, (t,2H), 5.40 (s, 2H), 6.68-6.72 (dd, 1H), 6.92 (d, 1H), 7.03 (d, 1H),7.27-7.42 (m, 6H), 7.83 (d, 1H), 8.03 (s, 1H), 8.15 (d, 1H), 8.41 (s,1H), 9.78 (s, 1H), 11.45 (s, 1H), 11.98 (br s, 1H)

Example 142 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(2-dimethylamino-ethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 5 mg, 22%.

LC/MS: RT=1.53 Min (254 nm), m/z=497 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.22 (s, 6H), 2.63 (t, 2H), 4.02 (t, 2H), 5.4 (s,2H), 6.7-6.74 (dd, 1H), 6.93 (d, 1H), 7.03 (d, 1H), 7.26-7.42 (m, 6H),7.82 (d, 1H), 8.04 (s, 1H), 8.14 (d, 1H), 8.41 (s, 1H), 9.78 (s, 1H),11.45 (s, 1H), 11.98 (br s, 1H)

Example 143 1-Benzyl-1H-pyrazole-4-carboxylic acid{6-oxo-5-[5-(3-piperidin-1-yl-propoxy)-1H-indol-2-yl]-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 13 mg, 30%.

LC/MS: RT=1.62 Min (254 nm), m/z=551 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.37-1.41 (br m, 2H), 1.46-1.54 (m, 4H), 1.85(quintet, 2H), 2.30-2.36 (br m, 4H), 2.39 (t, 2H), 3.98 (t, 2H), 5.40(s, 2H), 6.68-6.72 (dd, 1H), 6.92 (d, 1H), 7.01 (d, 1H), 7.26-7.42 (m,6H), 7.82 (d, 1H), 8.03 (s, 1H), 8.15 (d, 1H), 8.40 (s, 1H), 9.78 (s,1H), 11.45 (s, 1H), 11.98 (br s, 1H)

Example 144 1-Benzyl-1H-pyrazole-4carboxylic acid{6-oxo-5-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-yl]-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 14 mg, 42%.

LC/MS: RT=1.53 Min (254 nm), m/z=523 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.68 (m, 4H), 2.52 (m, obscured by DMSO peak, 4H),2.78 (t, 2H), 4.04 (t, 2H), 5.40 (s, 2H), 6.68-6.72 (dd, 1H), 6.92 (d,1H), 7.02 (d, 1H), 7.26-7.42 (m, 6H), 7.82 (d, 1H), 8.04 (s, 1H), 8.15(d, 1H), 8.41 (s, 1H), 9.78 (s, 1H), 11.46 (s, 1H), 11.98 (br s, 1H)

Example 145 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(3-dimethylamino-propoxy)-1H-indol-2-yl]-6oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 14 mg, 28%.

LC/MS: RT=1.55 Min (254 nm), m/z=511 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.85 (quintet, 2H), 2.15 (s, 6H), 2.38 (t, 2H), 3.98(t, 2H), 5.40 (s, 2H), 6.68-6.72 (dd, 1H), 6.92 (d, 1H), 7.02 (d, 1H),7.26-7.42 (m, 6H), 7.82 (d, 1H), 8.04 (s, 1H), 8.15 (d, 1H), 8.40 (s,1H), 9.78 (s, 1H), 11.45 (s, 1H), 11.98 (br s, 1H)

Example 146 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-{5-[2-(4-methyl-piperazin-1-yl)-ethoxy]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 11 mg, 27%.

LC/MS: RT=1.52 Min (254 nm), m/z=552 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 2.14 (s, 3H), 2.20-2.40 (br m, 4H), 2.68 (t, 2H),4.05 (t, 2H), 5.40 (s, 2H), 6.69-6.74 (dd, 1H), 6.97 (d, 1H), 7.04 (d,1H), 7.27-7.42 (m, 6H), 7.83 (d, 1H), 8.04 (s, 1H), 8.15 (d, 1H), 8.40(s, 1H), 9.78 (s 1H), 11.45 (s, 1H), 11.98 (br s, 1H)

Example 147 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-{5-[2-(2,6-dimethyl-morpholin-4-yl)-ethoxy]-1H-indol-2-yl}-6oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 5 mg, 11%.

LC/MS: RT=0.93 Min (254 nm), m/z=567 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.04 (d, 6H), 1.72 (t, 2H), 2.67 (m, 2H), 2.84 (d,2H), 3.57 (m, 2H), 4.06 (t, 2H), 5.40 (s, 2H), 6.7-6.73 (dd, 1H), 6.93(d, 1H), 7.04 (d, 1H), 7.28-7.42 (m, 6H), 7.82 (d, 1H), 8.03 (s 1H),8.15 (d, 1H), 8.41 (s, 1H), 9.78 (s, 1H), 11.44 (s, 1H), 11.98 (br s,1H)

Example 148 1-Benzyl-1H-pyrazole-4-carboxylic acid(6-oxo-5-{5-[3-(2-oxo-pyrrolidin-1-yl)-propoxy]-1H-indole-2-yl}-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by preparative HPLC at pH 4 and isolatedas a yellow solid, 8 mg, 12%.

LC/MS: RT=1.08 Min (254 nm), m/z=551 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.85-1.95 (m, 4H), 2.20 (t, 2H), 3.35 (m, partiallyobscured by water peak, 4H), 3.90 (t, 2H), 5.40 (s, 2H), 6.7-6.73 (dd,1H), 6.94 (d, 1H), 7.00 (d, 1H), 7.28-7.42 (m, 6H), 7.82 (d, 1H), 8.00(s, 1H), 8.14 (d, 1H), 8.41 (s, 1H), 9.79, (s, 1H), 11.45 (s, 1H), 11.98(br s, 1H).

Example 149 1-Benzyl-1H-pyrazole-4-carboxylic acid{6-oxo-5-[5-(2-piperidin-1-yl-ethoxy)-1H-indol-2-yl]-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 16 mg, 33%.

LC/MS: RT=1.73 Min (270 nm), m/z=537 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.4 (m, 3H), 1.50 (m, 4H), 2.40 (m, 2H), 2.70 (m,3H), 4.0 (t, 2H), 5.40 (s, 2H), 6.70 (dd, 2H), 6.8 (s, 1H), 7.00 (s,1H), 7.3 (m, 5H), 7.80 (s, 1H), 8.0 (s, 1H), 8.10 (s, 1H), 8.40 (s, 1H),9.70 (s, 1H), 12.00 (br, 1H)

Example 150 1-(4-Isopropylbenzyl)-1H-pyrazole-4-carboxylicacid-{6-oxo-5-[5-(3-piperidin-1-ylpropoxy)-1H-indol-2-yl]-1,6-dihydropyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with diethyl ether, andisolated as a yellow solid, 70 mg, 35%.

LC/MS: RT=1.82 Min (270 nm), m/z=593 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.20 (d, 6H), 1.40 (br s, 2H), 1.55 (br s, 4H), 1.90(br m, 2H), 2.40 (br s, 4H), 2.90 (m, 1H), 4.00 (t, 2H), 5.35 (s, 2H),6.70 (dd, 1H), 6.95 (d, 1H), 7.05 (d, 1H), 7.25 (m, 4H), 7.40 (d, 1H),7.85 (d, 1H), 8.00 (s, 1H), 8.20 (d, 1H), 8.45 (s, 1H), 9.85 (s, 1H),11.44 (br s, 1H), 11.98 (br s, 1H).

Example 151 1-(4-tert-Butylbenzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(2-piperidin-1-ylethoxy)-1H-indol-2-yl)-6-oxo-1,6-dihydropyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with diethyl ether, andisolated as a yellow solid, 60 mg, 40%.

LC/MS: RT=1.84 Min (270 nm), m/z=593 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.30 (s, 9H), 1.45 (br m, 2H), 1.55 (m, 4H), 2.45(br s, 4H), 2.70 (t, 2H), 4.05 (t, 2H), 5.35 (s, 2H), 6.70 (dd, 1H),6.95 (d, 1H), 7.05 (d, 1H), 7.25 (d, 2H), 7.45 (m, 3H), 7.85 (d, 1H),8.00 (s, 1H), 8.20 (d, 1H), 8.45 (s, 1H), 9.85 (s, 1H), 11.44 (br s,1H).

Example 152 1-(4-Isopropylbenzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(2-piperidin-1-ylethoxy)-1H-indol-2-yl)-6-oxo-1,6-dihydropyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with diethyl ether, andisolated as a yellow solid, 60 mg, 47%.

LC/MS: RT=1.80 Min (270 nm), m/z=579 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.20 (d, 6H), 1.40 (br m, 2H), 1.55 (m, 4H), 2.45(br s, 4H), 2.70 (t, 2H), 2.90 (m, 1H), 4.10 (t, 2H), 5.35 (s, 2H), 6.70(dd, 1H), 6.95 (d, 1H), 7.05 (d, 1H), 7.25 (m, 4H), 7.40 (d, 1H), 7.85(d, 1H), 8.00 (s, 1H), 8.20 (d, 1H), 8.45 (s, 1H), 9.85 (s, 1H), 11.44(br s, 1H), 11.90 (br s, 1H).

Example 153 1-(4-tert-Butylbenzyl)-1H-pyrazole-4-carboxylicacid-{6-oxo-5-[5-(3-piperidin-1-ylpropoxy)-1H-indol-2-yl]-1,6-dihydropyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by preparative HPLC at pH 4 to give theproduct as a yellow solid, 50 mg, 28%.

LC/MS: RT=1.08 Min (270 nm), m/z=607 [M+H]. Total run time 1.9 min(super short pos).

¹H NMR (d₆ DMSO): δ 1.30 (s, 9H), 1.40 (br m, 2H), 1.55 (m, 4H), 1.90(m, 2H), 2.45 (br s, 4H), 4.00 (t, 2H), 5.35 (s, 2H), 6.70 (dd, 1H),6.95 (d, 1H), 7.00 (d, 1H), 7.20 (d, 2H), 7.40 (m, 3H), 7.85 (d, 1H),8.00 (s, 1H), 8.20 (d, 1H), 8.45 (s, 1H), 9.85 (s, 1H), 11.46 (br s,1H).

Example 154 1-(4-tert-Butylbenzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(2-dimethylaminoethoxy)-1H-indol-2-yl)-6-oxo-1,6-dihydropyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with diethyl ether, andisolated as a yellow solid, 65 mg, 40%.

LC/MS: RT=1.82 Min (270 nm), m/z=581 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.00 (br t, 6H), 1.30 (s, 9H), 2.60 (br s, 4H), 2.85(br s, 2H), 4.00 (br s, 2H), 5.35 (s, 2H), 6.75 (dd, 1H), 6.95 (d, 1H),7.05 (d, 1H), 7.25 (d, 2H), 7.40 (m, 3H), 7.85 (d, 1H), 8.00 (s, 1H),8.20 (d, 1H), 8.45 (s, 1H), 9.85 (s, 1H), 11.44 (br s, 1H), 11.98 (br s,1H).

Example 155 1-(4-Isopropylbenzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(2-diethylaminoethoxy)-1H-indol-2-yl)-6-oxo-1,6-dihydropyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with diethyl ether, andisolated as a yellow solid, 110 mg, 55%.

LC/MS: RT=1.78 Min (270 nm), m/z=567 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.00 (t, 6H), 1.20 (d, 6H), 2.60 (br q, 4H), 2.85(br s, 2H), 2.90 (m, 1H), 4.00 (t, 2H), 5.35 (s, 2H), 6.70 (dd, 1H),6.95 (d, 1H), 7.05 (d, 1H), 7.25 (m, 4H), 7.40 (d, 1H), 7.85 (d, 1H),8.00 (s, 1H), 8.20 (d, 1H), 8.45 (s, 1H), 9.85 (s, 1H), 11.44 (br s,1H), 11.98 (br s, 1H).

Example 156 1-(4-tert-butylbenzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(3-dimethylaminopropoxy)-1H-indol-2-yl)-6-oxo-1,6-dihydropyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with diethyl ether, andisolated as a yellow solid, 80 mg, 56%.

LC/MS: RT=1.80 Min (270 nm), m/z=567 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.30 (s, 9H), 1.90 (m, 2H), 2.20 (s, 6H), 2.40 (t,2H), 4.00 (t, 2H), 5.35 (s, 2H), 6.75 (dd, 1H), 6.95 (d, 1H), 7.05 (d,1H), 7.25 (d, 2H), 7.40 (m, 3H), 7.85 (d, 1H), 8.00 (s, 1H), 8.20 (d,1H), 8.45 (s, 1H), 9.85 (s, 1H), 11.44 (br s, 1H), 11.94 (br s, 1H).

Example 157 1-(4-Isopropylbenzyl)-1H-pyrazole-4-carboxylic acid{5-[5-(3-dimethylaminopropoxy)-1H-indol-2-yl)-6-oxo-1,6-dihydropyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 121.

The title compound was purified by trituration with diethyl ether, andisolated as a yellow solid, 115 mg, 68%.

LC/MS: RT=1.75 Min (270 nm), m/z=553 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.25 (d, 6H), 1.75 (m, 2H), 2.15 (s, 6H), 2.40 (t,2H), 2.90 (m, 1H), 4.00 (t, 2H), 5.35 (s, 2H), 6.70 (dd, 1H), 6.95 (d,1H), 7.05 (d, 1H), 7.25 (m, 4H), 7.40 (d, 1H), 7.85 (d, 1H), 8.00 (s,1H), 8.20 (d, 1H) 8.45 (s, 1H), 9.85 (s, 1H), 11.44 (br s, 1H), 11.96(br s, 1H).

Example 158 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[4-(2-amino-ethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115, except1H-Indol-4-ol was used and the alternative deprotection method describedfor Example 108 was adopted.

The title compound was purified by trituration with ethyl acetate, andisolated as a yellow solid, 7 mg, 10%.

LC/MS: RT=1.48 Min (270 nm), m/z=469 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₄ MeOD): δ 3.17 (t, 2H), 4.20 (t, 2H), 5.40 (s, 2H), 6.52 (dd,1H), 7.06 (m, 2H), 7.20 (s, 1H), 7.33 (m, 5H), 7.86 (d, 1H), 8.05 (s,1H), 8.23 (d, 1H), 8.26 (s, 1H).

Example 159 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[4-(2-dimethylamino-ethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115, except1H-Indol-4-ol was used and the alternative deprotection method describedfor Example 108 was adopted.

The title compound was purified by trituration with ethyl acetate, andisolated as a yellow solid, 22 mg, 29%.

LC/MS: RT=1.51 Min (270 nm), m/z=497 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₄ MeOD): δ 2.47 (s, 6H), 2.94 (t, 2H), 4.29 (t, 2H), 5.43 (s,2H), 6.53 (d, 1H), 7.06 (m, 2H), 7.17 (s, 1H), 7.40 (m, 5H), 7.95 (d,1H), 8.09 (s, 1H), 8.23 (d, 1H), 8.29 (s, 1H).

Example 160 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6,following the same procedures as for Example 20, apart from a modifiedcoupling procedure in Step 4 which utilised intermediate (6h).

Preparation of 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carbonyl chloride(6h)

A 20 mL microwave vial was charged with 1H-pyrazole-4-carboxylic acidethyl ester (1 g, 7.1 mmol), (R)-1-phenylethanol (1.31 mL, 10.7 mmol),triphenylphosphine (3 g, 11.4 mmol) and tetrahydrofuran (15 mL). Thereaction was stirred at ambient temperature for 10 minutes before addingdiisopropyl azodicarboxylate (2.25 mL, 11.14 mmol) with cooling. Thevial was heated under microwave irradiation at 140° C. for 15 mins.After cooling, the solvent was removed in vacuo and the residue purifiedby flash chromatography on SiO₂ with hexane—30% ethyl acetate/hexane(gradient) to afford intermediate (6f),1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid ethyl ester as anoil, 1.646 g, 94%.

Intermediate (6f), 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acidethyl ester (1.525 g, 6.2 mmol) was stirred in a mixture oftetrahydrofuran (20 mL) and water (20 mL). Lithium hydroxide (0.524 g,12.5 mmol) was added and the reaction stirred at ambient temperature for24 hours. The reaction mixture was reduced in volume and extracted withdiethyl ether (3×20 mL). The aqueous layer was carefully acidified usingan aqueous 6N hydrochloric acid solution. The resulting precipitate wasfiltered, washed with copious amounts of water and dried in vacuo toafford intermediate (6g),1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid as a white solid,0.664 g, 49%.

Intermediate (6g), 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid(0.5 g, 2.31 mmol) was stirred in toluene (20 mL) at RT and thionylchloride (0.34 mL, 4.62 mmol) was added. The reaction mixture was slowlyheated to 90° C. and heating continued for 3 hrs. After cooling thereaction was concentrated in vacuo. Toluene was added to the residue andconcentrated in vacuo. This was repeated a further three times and thetitle compound, intermediate (6h),1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carbonyl chloride, was isolated asan oil, 0.544 g, quantitative.

Modified Procedure for Step 4.

Intermediate (6c),2-[5-Amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (100 mg, 0.22 mmol) was stirred in dichloromethane(5 mL) at RT with triethylamine (0.092 mL, 0.66 mmol). The reactionmixture was cooled to 5° C. and then a solution of intermediate (6h),1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carbonyl chloride, (54 mg, 0.231mmol) in dichloromethane (1 mL) was added drop wise. After addition thereaction was stirred at RT for 1 hour and then the reaction mixture wasconcentrated in vacuo and the residue partitioned between ethyl acetate(10 mL) and aqueous saturated sodium hydrogen carbonate solution (10mL). The organic layer was separated and the aqueous was extracted witha further portion of ethyl acetate (10 mL). The combined ethyl acetatelayers were washed with brine, dried (Na₂SO₄) and concentrated in vacuo.The resultant crude product was purified by flash chromatography on SiO₂eluting with hexane—50% ethyl acetate/hexane (gradient) to afford thedesired intermediate,2-(1-Methyl-2-oxo-5-{[1-((S)-1-phenyl-ethyl)-1H-pyrazole-4-carbonyl]-amino}-1,2-dihydro-pyridin-3-yl)-indole-1-carboxylicacid tert-butyl ester, 0.108 g, 76%.

The title compound was purified by flash chromatography on SiO₂ elutingwith dichloromethane—10% methanol/dichloromethane (gradient) to affordthe desired title compound as a yellow solid, 22 mg, 31%.

LC/MS: RT=2.07 Min (270 nm), m/z=424 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.84 (d, 3H), 5.69 (q, 1H), 6.98 (m, 1H), 7.05-7.09(m, 2H), 7.28-7.39 (m, 5H), 7.49-7.54 (m, 2H), 7.81 (d, 1H), 8.04 (s,1H), 8.18 (d, 1H), 8.45 (s, 1H), 9.77 (s, 1H), 11.56 (s, 1H), 12.00 (brs, 1H).

Example 161 1-((R)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 6,following the same procedures as for Example 160, except intermediate(6k), 1-((R)-1-Phenyl-ethyl)-1H-pyrazole-4-carbonyl chloride, was usedin the coupling procedure in Step 4. Intermediate (6k),1-((R)-1-Phenyl-ethyl)-1H-pyrazole-4-carbonyl chloride, was synthesisedusing the same procedures as for intermediate (6h), but starting from(S)-1-phenylethanol.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 34 mg, 45%.

LC/MS: RT=2.07 Min (270 nm), m/z=424 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.84 (d, 3H), 5.69 (q, 1H), 6.98 (m, 1H), 7.05-7.09(m, 2H), 7.28-7.39 (m, 5H), 7.49-7.54 (m, 2H), 7.81 (d, 1H), 8.04 (s,1H), 8.18 (d, 1H), 8.45 (s, 1H), 9.77 (s, 1H), 11.56 (s, 1H), 12.00 (brs, 1H).

Example 162 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4carboxylic acid[6-oxo-5-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37, reactingintermediate (8d),2-[5-Amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(tert-butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylicacid tert-butyl with intermediate (6h),1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carbonyl chloride in the couplingstep as described for Example 160.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 131 mg, 71%.

LC/MS: RT=1.58 Min (270 nm), m/z=521 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.37-1.50 (m, 6H), 1.84 (d, 3H), 2.31 (m, 4H), 3.44(s, 2H), 5.69 (q, 1H), 7.00-7.03 (m, 2H), 7.28-7.44 (m, 7H), 7.82 (d,1H), 8.03 (s, 1H), 8.15 (d, 1H), 8.45 (s, 1H), 9.78 (s, 1H), 11.50 (s,1H), 11.97 (br s, 1H).

Example 163 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid{5-[5-(cis-2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 162. The titlecompound was purified by trituration with acetonitrile, and isolated asa yellow solid, 25 mg, 38%.

LC/MS: RT=1.59 Min (270 nm), m/z=551 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.00 (d, 6H), 1.62 (t, 2H), 1.84 (d, 3H), 2.68 (d,2H), 3.47 (s, 2H), 3.54 (m, 2H), 5.70 (q, 1H), 7.01-7.04 (m, 2H),7.28-7.46 (m, 7H), 7.82 (d, 1H), 8.04 (s, 1H), 8.16 (d, 1H), 8.45 (s,1H), 9.78 (s, 1H), 11.53 (s, 1H), 11.99 (br s, 1H).

Example 164 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-fluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 162. The titlecompound was purified by trituration with acetonitrile, and isolated asa yellow solid, 37 mg, 57%.

LC/MS: RT=1.59 Min (270 nm), m/z=539 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.68 (m, 2H), 1.79 (m, 2H), 1.84 (d, 3H), 2.28 (m,2H), 2.50 (m, 2H), 3.50 (s, 2H), 4.60-4.72 (m, 1H), 5.70 (q, 1H),7.01-7.04 (m, 2H), 7.28-7.45 (m, 7H), 7.82 (d, 1H), 8.03 (s, 1H), 8.15(d, 1H), 8.45 (s, 1H), 9.78 (s, 1H), 11.53 (s, 1H), 11.99 (br s, 1H).

Example 165 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-methyl-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 162. The titlecompound was purified by trituration with acetonitrile, and isolated asa yellow solid, 40 mg, 54%.

LC/MS: RT=1.65 Min (270 nm), m/z=535 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.87 (d, 3H), 1.12 (m, 2H), 1.30 (m, 1H), 1.54 (m,2H), 1.84 (d, 3H), 1.87 (m, 2H), 2.78 (m, 2H), 3.45 (s, 2H), 5.70 (q,1H), 7.00-7.03 (m, 2H), 7.28-7.44 (m, 7H), 7.82 (d, 1H), 8.03 (s, 1H),8.15 (d, 1H), 8.45 (s, 1H), 9.78 (s, 1H), 11.51 (s, 1H), 11.99 (br s,1H).

Example 166

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 37, reactingintermediate (8d),2-[5-Amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(tert-butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylicacid tert-butyl with intermediate (6k),1-((R)-1-Phenyl-ethyl)-1H-pyrazole-4-carbonyl chloride in the couplingstep as described for Example 161.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 47 mg, 55%.

LC/MS: RT=1.61 Min (270 nm), m/z=551 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.01 (d, 6H), 1.62 (t, 2H), 1.84 (d, 3H), 2.68 (m,2H), 3.47 (s, 2H), 3.54 (m, 2H), 5.70 (q, 1H), 7.01-7.04 (m, 2H),7.28-7.46 (m, 7H), 7.82 (d, 1H), 8.03 (s, 1H), 8.15 (d, 1H), 8.45 (s,1H), 9.78 (s, 1H), 11.53 (s, 1H), 11.99 (br s, 1H).

Example 167 1-((R)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-methyl-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 166. The titlecompound was purified by trituration with acetonitrile, and isolated asa yellow solid, 54 mg, 56%.

LC/MS: RT=1.66 Min (270 nm), m/z=535 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.87 (d, 3H), 1.12 (m, 2H), 1.30 (m, 1H), 1.54 (m,2H), 1.84 (d, 3H), 1.87 (m, 2H), 2.78 (m, 2H), 3.46 (s, 2H), 5.70 (q,1H), 7.00-7.03 (m, 2H), 7.28-7.44 (m, 7H), 7.82 (d, 1H), 8.03 (s, 1H),8.15 (d, 1H), 8.45 (s, 1H), 9.78 (s, 1H), 11.51 (s, 1H), 11.99 (br s,1H).

Example 168 1-((R)-1-Phenyl-ethyl)-1H-pyrazole-4carboxylic acid[6-oxo-5-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 166. The titlecompound was purified by trituration with acetonitrile, and isolated asa yellow solid, 48 mg, 58%.

LC/MS: RT=1.60 Min (270 nm), m/z=521 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.37-1.50 (m, 6H), 1.84 (d, 3H), 2.31 (m, 4H), 3.44(s, 2H), 5.70 (q, 1H), 7.00-7.03 (m, 2H), 7.28-7.44 (m, 7H), 7.82 (d,1H), 8.03 (s, 1H), 8.15 (d, 1H), 8.45 (s, 1H), 9.78 (s, 1H), 11.51 (s,1H), 11.99 (br s, 1H).

Example 169 1-((R)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid{5-[5-(4-fluoro-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 166. The titlecompound was purified by trituration with acetonitrile, and isolated asa yellow solid, 49 mg, 53%.

LC/MS: RT=1.56 Min (270 nm), m/z=539 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 1.68 (m, 2H), 1.79 (m, 2H), 1.84 (d, 3H), 2.28 (m,2H), 2.52 (m, 2H), 3.50 (s, 2H), 4.60-4.72 (m, 1H), 5.70 (q, 1H),7.01-7.04 (m, 2H), 7.28-7.45 (m, 7H), 7.83 (d, 1H), 8.03 (s, 1H), 8.16(d, 1H), 8.45 (s, 1H), 9.78 (s, 1H), 11.52 (s, 1H), 11.99 (br s, 1H).

Example 170 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(5-{1(2-dimethylamino-ethyl)-methyl-aminol-methyl}-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 28 mg, 24%.

LC/MS: RT=1.45 Min (270 nm), m/z=522 [M−H]. Total run time 3.75 min(short neg).

¹H NMR (d₆ DMSO): δ 2.15 (s, 9H), 2.42 (s, 4H), 3.52 (s, 2H), 5.41 (s,2H), 6.98-7.06 (m, 2H), 7.25-7.45 (m, 7H), 7.82 (s, 1H), 8.04 (s, 1H),8.17 (d, 1H), 8.42 (s, 1H), 9.81 (br s, 1H), 11.52 (br s, 1H), 12.0 (brs, 1H).

Example 171 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-((S)-2-methyl-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 58 mg, 56%.

LC/MS: RT=1.68 Min (270 nm), m/z=519 [M−H]. Total run time 3.75 min(short neg).

¹H NMR (d₆ DMSO): δ 1.15 (d, 3H), 1.22-1.36 (m, 4H), 1.88 (m, 1H), 2.3(m, 1H), 2.65 (m, 1H), 3.12 (d, 1H), 4.0 (d, 1H), 5.4 (s, 2H), 6.99-7.04(m, 2H), 7.27-7.44 (m, 7H), 7.82 (m, 1H), 8.03 (s, 1H), 8.15 (d, 1H),8.41 (s, 1H), 9.8 (br s, 1H), 11.5 (br s, 1H), 11.99 (br s, 1H).

Example 172 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-((R)-3-dimethylamino-pyrrolidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 42 mg, 31%.

LC/MS: RT=1.45 Min (270 nm), m/z=534 [M−H]. Total run time 3.75 min(short neg).

¹H NMR (d₆ DMSO): δ 1.58 (m 1H), 1.82 (m, 1H), 2.05 (s, 6H), 2.22 (m,1H), 2.42 (m, 1H), 2.56 (m, 1H), 2.66 (m, 2H), 3.58 (dd, 2H), 5.41 (s,2H), 7.01 (m, 2H), 7.25-7.45 (m, 7H), 7.82 (s, 1H), 8.03 (s, 1H), 8.17(s, 1H), 8.41 (s, 1H), 9.8 (br s, 1H), 11.5 (br s, 1H), 11.99 (br s,1H).

Example 173 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-((R)-2-methyl-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 20 mg, 20%.

LC/MS: RT=1.69 Min (270 nm), m/z=519 [M−H]. Total run time 3.75 min(short neg).

¹H NMR (d₆ DMSO): δ 1.15 (d, 3H), 1.22-1.36 (m, 4H), 1.88 (m, 1H), 2.3(m, 1H), 2.65 (m, 1H), 3.12 (d, 1H), 4.0 (d, 1H), 5.4 (s, 2H), 6.99-7.04(m, 2H), 7.27-7.44 (m, 7H), 7.82 (m, 1H), 8.03 (s, 1H), 8.15 (d, 1H),8.41 (s, 1H), 9.82 (br s, 1H), 11.51 (br s, 1H), 11.99 (br s, 1H).

Example 174 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-((R)-3-fluoro-pyrrolidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 20 mg, 20%.

LC/MS: RT=1.63 Min (270 nm), m/z=509 [M−H]. Total run time 3.75 min(short neg).

¹H NMR (d₆ DMSO): δ 1.77-1.93 (m, 1H), 2.05-2.2 (m, 1H), 2.3 (q, 1H),2.53-2.64 (m, 1H), 2.7-2.82 (m, 2H), 3.63 (s, 2H), 5.18 (dt, 1H), 5.4(s, 2H), 7.0-7.07 (m, 2H), 7.27-7.46 (m, 7H), 7.82 (d, 1H), 8.03 (s,1H), 8.17 (d, 1H), 8.41 (s, 1H), 9.79 (s, 1H), 11.52 (br s, 1H), 12.01(br s, 1H).

Example 175 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-((S)-3-fluoro-pyrrolidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 76 mg, 81%.

LC/MS: RT=1.62 Min (270 nm), m/z=509 [M−H]. Total run time 3.75 min(short neg).

¹H NMR (d₆ DMSO): δ 1.77-1.93 (m, 1H), 2.05-2.2 (m, 1H), 2.3 (q, 1H),2.53-2.64 (m, 1H), 2.7-2.82 (m, 2H), 3.63 (s, 2H), 5.18 (dt, 1H), 5.4(s, 2H), 7.0-7.07 (m, 2H), 7.27-7.46 (m, 7H), 7.82 (d, 1H), 8.03 (s,1H), 8.17 (d, 1H), 8.41 (s, 1H), 9.8 (s, 1H), 11.52 (br s, 1H), 12.01(br s, 1H).

Example 176 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(5-{[(3-dimethylamino-2,2-dimethyl-propyl)-ethyl-amino]-methyl}-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51.

Purification by trituration with acetonitrile afforded the titlecompound as a yellow solid, 30 mg, 43%

LC/MS: RT=1.49 Min (270 nm), m/z=580 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.86 (s, 6H), 0.92 (t, 3H), 2.09 (s, 2H), 2.19 (s,6H), 2.31 (s, 2H), 2.42 (q, 2H), 3.64 (s, 2H), 5.41 (s, 2H), 7.01 (s,1H), 7.11 (dd, 1H), 7.28-7.45 (m, 7H), 7.80 (d, 1H), 8.03 (s, 1H), 8.16(d, 1H), 8.41 (s, 1H), 9.79 (s, 1H), 11.49 (s, 1H), 11.99 (br s, 1H)

Example 177 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(cis-2,6-dimethyl-piperidin-1-ylmethyl)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 8,following the same experimental procedures as for Example 51, with thefollowing modification. Deprotection of intermediate (8e),5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester, in the usual manner, yielded2-[5-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-hydroxymethyl-indole-1-carboxylicacid tert-butyl ester. DIPEA (1534, 0.9 mmol) and2-[5-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-hydroxymethyl-indole-1-carboxylicacid tert-butyl ester (0.2 g, 0.3 mmol) were stirred in1,2-dichloroethane (5 mL) and cooled to 0° C. Methanesulfonyl chloride(274, 0.36 mmol) was added drop wise at 0° C. and stirred for a further2 hours at 0° C. cis-2,6-Dimethylpiperidine (118 μL 0.9 mmol) was addeddrop wise at 0° C. and then the reaction was allowed to attain ambienttemperature. The reaction mixture was heated at reflux overnightfollowed by cooling to ambient temperature. The reaction mixture wasdiluted with ethyl acetate (30 mL), washed with water (30 mL), saturatedsodium hydrogen carbonate solution (30 mL), brine, dried (Na₂SO₄) andconcentrated in vacuo. The resultant crude product was taken up inmethanol (1 mL) and loaded onto a 5 g SCX column. The column was flushedwith methanol and then eluted with ammonia solution 7N in methanol. Theeluent was concentrated in vacuo to afford the title compound as a lightbrown solid, 120 mg, 53%.

Global deprotection in the usual manner afforded the title compoundwhich was purified by trituration with diethyl ether, and isolated as ayellow solid, 20 mg, 24%. LC/MS: RT=1.72 Min (270 nm), m/z=535 [M+H].Total run time 3.75 min (short pos).

¹H NMR (d₆ DMSO): δ 1.02 (d, 6H), 1.26 (m, 3H), 1.53-1.60 (m, 3H), 2.45(m, 2H), 3.78 (s, 2H), 5.41 (s, 2H), 7.00 (s, 1H), 7.08 (d, 1H),7.28-7.40 (m, 6H), 7.49 (s, 1H), 7.80 (s, 1H), 8.03 (s, 1H), 8.14 (d,1H), 8.41 (s, 1H), 9.79 (s, 1H), 11.45 (s, 1H), 11.98 (br s, 1H).

Example 178 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(3-diethylamino-2,2-dimethyl-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 50 mg, 47%.

LC/MS: RT=1.78 Min (270 nm), m/z=567.3 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.90 (t, 6H), 0.95 (s, 6H), 2.35 (s, 2H), 2.50 (q,4H), 3.65 (s, 2H), 5.40 (s, 2H), 6.70 (dd, 1H), 6.90 (d, 1H), 7.00 (d,1H), 7.25-7.45 (m, 6H), 7.85 (d, 1H), 8.05 (s, 1H), 8.15 (d, 1H), 8.40(s, 1H), 9.80 (s, 1H), 11.40 (s, 1H), 12.00 (br s, 1H).

Example 179 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115. In thisinstance the chloroalkyl intermediate,(2-chloro-2-methyl-propyl)-dimethyl-amine hydrochloride, required forStep 6 was not commercially available and was synthesised according tothe following methodology.

Preparation of (2-chloro-2-methyl-propyl)-dimethyl-amine hydrochloride

2-Dimethylamino-2-methyl-propan-1-ol as an 80% solution in water (10 mL,9.1 g, 78 mmol) was dissolved in toluene (100 mL) and then afterstirring for 30 mins, the organic layer separated, dried over Mg₂SO₄ andthen concentrated to a volume of approximately 50 mL. Thionyl chloride(95 mmol, 6.9 mL, 11.3 g) was added to this solution and the mixtureheated at 80° C. for 3 hrs. After cooling, the mixture was concentratedin vacuo. Anhydrous toluene was added and the mixture was concentratedin vacuo. This process was repeated a further three times with tolueneand once with isohexane. The residue obtained was slurried in diethylether, separated via filtration and washed with copious amounts ofdiethylether before being dried in vacuo at RT. The compound obtainedwas a mixture of the desired title compound(2-chloro-2-methyl-propyl)-dimethyl-amine hydrochloride (70%) and theisomer (2-chloro-1,1-dimethyl-ethyl)-dimethyl-amine (30%) by NMR. Thetotal yield was 5.23 g (49%).

This mixture containing 70% desired intermediate and 30% undesiredisomer was used in the subsequent alkylation step without furtherpurification and so a mixture of two possible products was obtained.These two products were duly separated, prior to global deprotection, byflash chromatography on SiO₂ and the desired product was eluted usingdichloromethane—10% methanol/dichloromethane (gradient). The undesiredproduct of this reaction remained on the column.

The title compound was purified by trituration with diethyl ether, andisolated as a yellow solid, 58 mg, 64%.

LC/MS: RT=1.65 Min (270 nm), m/z=523 [M−H]. Total run time 3.75 min(short neg).

¹H NMR (d₆ DMSO): δ 1.21 (s, 6H), 2.34 (s, 6H) 5.41 (s, 2H), 6.74 (dd,1H), 6.97 (s, 1H), 7.1 (s, 1H), 7.27-7.41 (m, 6H), 7.82 (d, 1H), 8.03(s, 1H), 8.15 (d, 1H), 8.42 (s, 1H), 9.8 (br s, 1H), 11.48 (s, 1H), 12.0(br s, 1H).

Example 180 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(2,2-dimethyl-3-pyrrolidin-1-yl-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115. In thisinstance the chloroalkyl intermediate,1-(3-chloro-2,2-dimethyl-propyl)-pyrrolidine, required for Step 6, wasnot commercially available and was synthesised according to thefollowing methodology.

Preparation of 1-(3-Chloro-2,2-dimethyl-propyl)-pyrrolidine

3-Chloro-2,2-dimethyl-propionyl chloride (0.5 g, 3.2 mmol) was stirredin dichloromethane (20 mL) at RT with triethylamine (0.9 mL, 6.4 mmol).The reaction mixture was cooled to 5° C. and then pyrrolidine (0.32 mL,3.9 mmol), was added drop wise. After addition the reaction was stirredat RT for 1 hr, and then the reaction mixture was washed with saturatedsodium hydrogen carbonate solution (2×50 mL), brine (50 ml), dried(Na₂SO₄) and concentrated in vacuo to afford3-chloro-2,2-dimethyl-1-pyrrolidin-1-yl-propan-1-one as a yellow solid,0.576 g, 94%.

To this intermediate,3-chloro-2,2-dimethyl-1-pyrrolidin-1-yl-propan-1-one (0.57 g, 3 mmol) inanhydrous THF (20 mL) was slowly added a 1M anhydrous THF solution oflithium aluminium hydride (7.5 mL, 7.5 mmol) at room temperature. Theresulting clear solution was stirred overnight at room temperature undernitrogen to give a cloudy suspension. Water (0.3 mL) was carefully addedto the reaction mixture followed by 15% w/v aqueous sodium hydroxydesolution (0.3 mL) and water (0.9 mL). The reaction was filtered and thefiltrate evaporated to dryness to give the title compound which was usedwithout further purification.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 104 mg, 54%.

LC/MS: RT=1.77 Min (270 nm), m/z=565 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.98 (s, 6H), 1.63 (m, 4H), 2.45 (s, 2H), 2.53 (m,4H), 3.68 (s, 2H), 5.40 (s, 2H), 6.72 (dd, 1H), 6.92 (s, 1H), 7.01 (d,1H), 7.28-7.40 (m, 6H), 7.84 (d, 1H), 8.03 (s, 1H), 8.14 (d, 1H), 8.41(s, 1H), 9.79 (s, 1H), 11.44 (s, 1H), 11.98 (br s, 1H).

Example 181 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-{5-[3-(3,3-difluoro-pyrrolidin-1-yl)-2,2-dimethyl-propoxy]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115. In thisinstance the relevant chloroalkyl intermediate, required for Step 6, wasnot commercially available and was synthesised according to the protocolgiven for Example 180.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 20 mg, 10%.

LC/MS: RT=2.11 Min (270 nm), m/z=601 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.98 (s, 6H), 2.18 (m, 2H), 2.47 (s, 2H), 2.78 (t,2H), 2.94 (t, 2H), 3.67 (s, 2H), 5.41 (s, 2H), 6.72 (dd, 1H), 6.92 (s.1H), 7.02 (d, 1H), 7.28-7.41 (m, 6H), 7.84 (d, 1H), 8.03 (s, 1H), 8.14(d, 1H), 8.41 (s, 1H), 9.79 (s, 1H), 11.44 (s, 1H), 12.0 (br s, 1H).

Example 182 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-{5-[3-((R)-3-fluoro-pyrrolidin-1-yl)-2,2-dimethyl-propoxy]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115. In thisinstance the relevant chloroalkyl intermediate, required for Step 6, wasnot commercially available and was synthesised according to the protocolgiven for Example 180.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 30 mg, 17%.

LC/MS: RT=1.56 Min (270 nm), m/z=583 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.98 (s, 6H), 1.75-2.11 (m, 2H), 2.45 (m, 3H),2.73-2.86 (m, 3H), 3.68 (s, 2H), 5.05-5.17 (m, 1H), 5.41 (s, 2H), 6.72(dd, 1H), 6.92 (s, 1H), 7.02 (d, 1H), 7.28-7.41 (m, 6H), 7.84 (d, 1H),8.03 (s, 1H), 8.14 (d, 1H), 8.41 (s, 1H), 9.79 (s, 1H), 11.44 (s, 1H),11.99 (br s, 1H)

Example 183 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-{5-[3-((S)-3-fluoro-pyrrolidin-1-yl)-2,2-dimethyl-propoxyl]-1H-indol-2-yl}-6-oxo-1,6-dihydro-pyridin-3-yl)-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115. In thisinstance the relevant chloroalkyl intermediate, required for Step 6, wasnot commercially available and was synthesised according to the protocolgiven for Example 180.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 31 mg, 18%.

LC/MS: RT=1.57 Min (270 nm), m/z=583 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.98 (s, 6H), 1.77-2.11 (m, 2H), 2.45 (m, 3H),2.71-2.86 (m, 3H), 3.68 (s, 2H), 5.06-5.17 (m, 1H), 5.41 (s, 2H), 6.72(dd, 1H), 6.92 (s, 1H), 7.02 (d, 1H), 7.28-7.41 (m, 6H), 7.84 (d, 1H),8.03 (s, 1H), 8.14 (d, 1H), 8.41 (s, 1H), 9.79 (s, 1H), 11.44 (s, 1H),11.99 (br s, 1H)

Example 184 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(2,2-dimethyl-3-morpholin-4-yl-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115. In thisinstance the relevant chloroalkyl intermediate, required for Step 6, wasnot commercially available and was synthesised according to the protocolgiven for Example 180.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 16 mg, 18%.

LC/MS: RT=1.74 Min (270 nm), m/z=581 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.98 (s, 6H), 2.27 (s, 2H), 2.43 (m, 4H), 3.50 (m,4H), 3.67 (s, 2H), 5.41 (s, 2H), 6.72 (dd, 1H), 6.91 (s, 1H), 7.01 (d,1H), 7.28-7.40 (m, 6H), 7.84 (d, 1H), 8.03 (s, 1H), 8.14 (d, 1H), 8.41(s, 1H), 9.79 (s, 1H), 11.43 (s, 1H), 11.99 (br s, 1H).

Example 185 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(2,2-dimethyl-3-piperidin-1-yl-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115. In thisinstance the relevant chloroalkyl intermediate required for Step 6 wasnot commercially available and was synthesised according to the protocolgiven for Example 180.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 123 mg, 64%.

LC/MS: RT=1.79 Min (270 nm), m/z=579 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.94 (s, 6H), 1.30 (m, 2H), 1.42 (m, 4H), 2.22 (s,2H), 2.40 (m, 4H), 3.65 (s, 2H), 5.41 (s, 2H), 6.71 (dd, 1H), 6.92 (s,1H), 7.00 (d, 1H), 7.28-7.40 (m, 6H), 7.83 (d, 1H), 8.03 (s, 1H), 8.14(d, 1H), 8.41 (s, 1H), 9.79 (s, 1H), 11.43 (s, 1H), 11.97 (br s, 1H).

Example 186 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(1-diethylaminomethyl-cyclopropylmethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115. In thisinstance the chloroalkyl intermediate,1-(1-chloromethyl-cyclopropylmethyl)-pyrrolidine hydrochloride, requiredfor Step 6, was not commercially available and was synthesised accordingto the following methodology.

Preparation of 1-(1-chloromethyl-cyclopropylmethyl)-pyrrolidinehydrochloride

Oxalyl chloride (12.5 mL, 2M) in dichloromethane was added to a solutionof cyclopropane-1,1-dicarboxylic acid methyl ester (2.90 g, 20 mmol) indichloromethane (50 mL) at 0° C. (ice/water) and the solution stirred.DMF (100 μL) was added and the solution stirred for ˜2 hrs. at roomtemperature, to give a pale yellow solution. The solution wasconcentrated to a yellow semi-solid.

The semi-solid was taken up in THF (20 ml) and the solution cooled, 0°C. (ice/water), and pyrrolidine (6 mL, 71 mmol) was added slowly and theresulting suspension stirred for ˜60 mins. Ethyl acetate (150 mL) wasadded and the mixture washed with water (2×75 mL) and saturated aqueoussodium chloride solution (75 mL). The solution was dried over anhydrousmagnesium sulphate and concentrated to yield1-(pyrrolidine-1-carbonyl)-cyclopropanecarboxylic acid methyl ester as ayellow/brown oil 2.20 g, 55%.

Lithium aluminium hydride solution (20 mL, 1M) in THF was added slowlyto a solution of 1-(pyrrolidine-1-carbonyl)-cyclopropanecarboxylic acidmethyl ester (2.2 g, 11 mmol) in THF at 0° C. (ice/water), under anitrogen atmosphere, and the resulting solution stirred for ˜3 hrs atroom temperature. The solution was cooled, 0° C. (ice/water), and sodiumsulphate decahydrate (4.9 g, 15 mmol) was added portion-wise to give awhite suspension. Diethyl ether (25 mL) was added and the suspensionstirred for ˜18 hrs. at room temperature. The resulting suspension wasfiltered, through celite, and the solids washed with diethyl ether (2×50mL). The combined filtrates were concentrated to give(1-pyrrolidin-1-ylmethyl-cyclopropyl)-methanol as a pale yellow oil 1.45g, 84%.

Thionyl chloride (1 mL, 13.7 mmol) was added to a solution of(1-pyrrolidin-1-ylmethyl-cyclopropyl)-methanol (1.45 g, 9.3 mmol) intoluene (20 mL) to give a pale brown suspension. The suspension washeated, 110° C., for ˜3 hrs. to give a dark brown suspension. Theresulting suspension was allowed to cool and concentrated to a brownsolid. Tritruation with diethyl ether (40 mL) gave the desiredintermediate, 1-(1-chloromethyl-cyclopropylmethyl)-pyrrolidinehydrochloride as a brown powder 1.6 g, 82%.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 145 mg, 58%.

LC/MS: RT=1.76 Min (270 nm), m/z=565.3 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.40 (t, 2H), 0.60 (t, 2H), 0.95 (t, 6H), 2.45 (s,2H), 2.50 (q, 4H), 3.85 (s, 2H), 5.40 (s, 2H), 6.70 (dd, 1H), 6.90 (d,1H), 7.00 (d, 1H), 7.25-7.45 (m, 6H), 7.85 (d, 1H), 8.00 (s, 1H), 8.15(d, 1H), 8.40 (s, 1H), 9.80 (s, 1H), 11.40 (s, 1H), 11.95 (br s, 1H).

Example 187 1-Benzyl-1H-pyrazole-4-carboxylic acid {6-oxo5-[5-(1-pyrrolidin-1-ylmethyl-cyclopropylmethoxy)-1H-indol-2-yl]-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115. In thisinstance the relevant chloroalkyl intermediate, required for Step 6, wasnot commercially available and was synthesised according to the protocolgiven for Example 186.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 175 mg, 62%.

LC/MS: RT=1.73 Min (270 nm), m/z=563.3 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.40 (t, 2H), 0.50 (t, 2H), 1.65 (br s, 4H), 2.45(s, 2H), 2.50 (br s, 4H), 3.85 (s, 2H), 5.40 (s, 2H), 6.75 (dd, 1H),6.90 (d, 1H), 7.00 (d, 1H), 7.25-7.40 (m, 6H), 7.85 (d, 1H), 8.05 (s,1H), 8.15 (d, 1H), 8.40 (s, 1H), 9.80 (s, 1H), 11.40 (s, 1H), 11.95 (brs, 1H).

Example 188 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(1-dimethylaminomethyl-cyclopropylmethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide

The title compound was prepared by the route outlined in Scheme 11,following the same experimental procedures as for Example 115. In thisinstance the relevant chloroalkyl intermediate, required for Step 6, wasnot commercially available and was synthesised according to the protocolgiven for Example 186.

The title compound was purified by trituration with acetonitrile, andisolated as a yellow solid, 190 mg, 66%.

LC/MS: RT=1.71 Min (270 nm), m/z=537.3 [M+H]. Total run time 3.75 min(short pos).

¹H NMR (d₆ DMSO): δ 0.40 (q, 2H), 0.60 (q, 2H), 2.21 (s, 6H), 2.25 (s,2H), 3.85 (s, 2H), 5.40 (s, 2H), 6.70 (dd, 1H), 6.90 (d, 1H), 7.00 (d,1H), 7.25-7.45 (m, 6H), 7.85 (d, 1H), 8.05 (s, 1H), 8.15 (d, 1H), 8.45(s, 1H), 9.80 (s, 1H), 11.40 (s, 1H), 11.95 (br s, 1H).

General Procedures

All reagents obtained from commercial sources were used without furtherpurification. Anhydrous solvents were obtained from commercial sourcesand used without further drying. Flash chromatography was performed withpre-packed silica-gel cartridges (Strata Si-1, 61 Å, Phenomenex,Cheshire, UK or IST Flash II, 54 Å, Argonaut, Hengoed, UK). Thin layerchromatography was conducted with 5×10 cm plates coated with Merck Type60 F₂₅₄ silica-gel. Microwave heating was performed with a BiotageInitiator™ 2.0 instrument.

The compounds of the present invention were characterized by highperformance liquid chromatography-mass spectroscopy (HPLC-MS) on eitheran Agilent HP1200 Rapid Resolution Mass detector 6140 multi mode sourceM/z range 150 to 1000 amu or an Agilent HP1100 Mass detector 1946D ESIsource M/z range 150 to 1000 amu. The conditions and methods listedbelow are identical for both machines.

Column for 3.75 min run: Gemini 5 μm, C18, 30 mm×4.6 mm (Phenomenex).

Temperature: 35 C.

Column for 1.9 min run: LunaHST 2.5 μm, C18, 50×2 mm (Phenomenex).

Temperature: 55 C.

Mobile Phase: A−Water+10 mMol/ammonium formate+0.08% (v/v) formic acidat pH ca 3.5.

B−95% Acetonitrile+5% A+0.08% (v/v) formic acid

Injection Volume: 2 μL

-   -   “Short” method gradient table, either positive (pos) or positive        and negative (pos/neg) ionisation

Time (min) Solvent A (%) Solvent B (%) Flow (mL/min) 0 95 5 2 0.25 95 52 2.50 95 5 2 2.55 5 95 3 3.60 5 95 3 3.65 5 95 2 3.70 95 5 2 3.75 95 52

-   -   “Super Short” method gradient table, either positive (pos) or        positive and negative (pos/neg) ionisation

Time (min) Solvent A (%) Solvent B (%) Flow (mL/min) 0 95 5 1.1 0.12 955 1.1 1.30 5 95 1.1 1.35 5 95 1.7 1.85 5 95 1.7 1.90 5 95 1.1 1.95 95 51.1Detection: UV detection at 230, 254 and 270 nm.

The compounds of the present invention were also characterized byNuclear Magnetic Resonance (NMR). Analysis was performed with a BrukerDPX400 spectrometer and proton NMR spectra were measured at 400 MHz. Thespectral reference was the known chemical shift of the solvent. ProtonNMR data is reported as follows: chemical shift (δ) in ppm, followed bythe multiplicity, where s=singlet, d=doublet, t=triplet, q=quartet,m=multiplet, dd=doublet of doublets, dt=doublet of triplets, dm=doubletof multiplets, ddd=doublet of double doublets, td=triplet of doublets,qd=quartet of doublets and br=broad, and finally the integration.

Some compounds of the invention were purified by preparative HPLC. Thesewere performed on a Waters FractionLynx MS autopurification system, witha Gemini® 5 μm C18(2), 100 mm×20 mm i.d. column from Phenomenex, runningat a flow rate of 20 cm³ min⁻¹ with UV diode array detection (210-400nm) and mass-directed collection. Gradients used for each compound areshown in Table 1.

At pH 4: solvent A=10 mM ammonium acetate in HPLC grade water+0.08% v/vformic acid. Solvent B=95% v/v HPLC grade acetonitrile+5% v/v solventA+0.08% v/v formic acid.

At pH 9: solvent A=10 mM ammonium acetate in HPLC grade water+0.08% v/vammonia solution. Solvent B=95% v/v HPLC grade acetonitrile+5% v/vsolvent A+0.08% v/v ammonia solution.

The mass spectrometer was a Waters Micromass ZQ2000 spectrometer,operating in positive or negative ion electrospray ionisation modes,with a molecular weight scan range of 150 to 1000.

IUPAC chemical names were generated using AutoNom Standard.

Assay Protocols

(i) CHK1 Enzyme Assay

Assays for the CHK1 kinase activity were carried out by monitoring thephosphorylation of a synthetic peptide Chktide with the amino acidsequence, KKKVSRSGLYRSPSMPENLNRPR. The assay mixture containing theinhibitor and CHK1 enzyme was mixed together in a microtiter plate in afinal volume of 50 μl and incubated for 40 minutes at 30° C.

The assay mixture contained 0.01 mM unlabeled ATP, 0.5 μCi ³³P-γ-ATP,14.8 μM Chktide, 0.1 mg/mL BSA, 50 mM Hepes-NaOH pH 7.5 and 12.5 nMHis-CHK1 (Invitrogen) enzyme. The reaction was stopped by adding 50 μLof 50 mM phosphoric acid. 90 μL of the mixture was transferred to apre-wetted 96-well multi-screen MAPHNOB filtration plate (Millipore) andfiltered on a vacuum manifold. The filter plate was washed with 3successive additions of 200 μl 50 mM phosphoric acid and then with 100μL methanol. The filtration plate was dried for 10 min at 65° C.,scintillant added and phosphorylated peptide quantified in ascintillation counter (Trilux, PerkinElmer).

The compounds tested in the above assay were assigned to one of threeactivity ranges, namely A=IC₅₀<100 nM, B=IC₅₀>100 nM and <500 nM orC=IC₅₀>500 nM and <1500 nM as indicated in the table below.

Table of CHK1 Enzyme Activities Example Activity 1 A 2 B 3 C 4 A 5 B 6 B7 C 8 B 9 A 10 A 11 A 12 B 13 A 14 B 15 A 16 A 17 C 18 C 19 B 20 A 21 A22 A 23 A 24 A 25 B 26 A 27 A 28 A 29 A 30 B 31 A 32 B 33 B 34 C 35 A 36B 37 A 38 A 39 A 40 A 41 A 42 A 43 A 44 A 45 A 46 A 47 A 48 A 49 A 50 A51 A 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 A 60 A 61 A 62 A 63 A 64 A 65A 66 A 67 A 68 A 69 A 70 A 71 A 72 A 73 A 74 A 75 A 76 A 77 A 78 A 79 A80 A 81 A 82 A 83 A 84 A 85 A 86 A 87 A 88 A 89 A 90 A 91 A 92 A 93 A 94A 95 A 96 A 97 A 98 A 99 A 100 A 101 A 102 A 103 A 104 A 105 A 106 A 107A 108 A 109 A 110 B 111 A 112 A 113 A 114 A 115 A 116 A 117 A 118 A 119A 120 A 121 A 122 A 123 A 124 A 125 A 126 A 127 A 128 A 129 A 130 A 131A 132 A 133 A 134 A 135 A 136 A 137 A 138 A 139 A 140 A 141 A 142 A 143A 144 A 145 A 146 A 147 A 148 A 149 A 150 A 151 A 152 A 153 A 154 C 155A 156 A 157 A 158 A 159 A 160 B 161 A 162 A 163 A 164 A 165 A 166 A 167A 168 A 169 A 170 A 171 A 172 A 173 A 174 A 175 A 176 A 177 A 178 A 179A 180 A 181 A 182 A 183 A 184 A 185 A 186 A 187 A 188 A(ii) CHK1 Cellular Assay—Gemcitabine EC₅₀ Assay

The gemcitabine EC₅₀ assay was developed as a rapid method for screeningCHK1 inhibitors to determine their relative cell activity. This assayutilises a feature of the effect of CHK1 inhibitors on gemcitabinetoxicity. In the absence of a CHK1 inhibitor, gemcitabine actspredominantly as an anti-metbolite and therefore induces very littlecell death, even at high concentrations. This can be as high as 70-80%survival at concentrations in excess of 1 μM. However, in the presenceof a CHK1 inhibitor, the mechanism of action of gemcitabine switches toa more classical cytotoxic mode of action. For example, the fraction ofcells surviving can be reduced to around 30% and below.

Concentrations of gemcitabine can be selected that in the absence of aCHK1 inhibitor, have no effect on cell survival but in the presence of aCHK1 inhibitor are highly cytotoxic. 10000 HT29 cells were plated perwell of a 96 well plate and allowed to attach at 37° C. in a 5% CO2humidified incubator for 18 hours. CHK1 inhibitors were then titrated inthe presence of 10, 15 and 20 nM gemcitabine for 72 hours and the EC₅₀determined by staining with sulforhodamine B (SRB) and determining theabsorbance at 540 nm.

The compounds were tested in the above assay in the presence ofgemcitabine at 10 nM, and assigned to one of two activity ranges, namelyA=EC₅₀<100 nM or B=EC₅₀>100 nM and <500 nM as indicated in the tablebelow.

Table of CHK1 Cellular Activities Example Activity 20 B 38 B 49 A 52 A71 A 78 A 87 A 120 A 166 A 171 A 173 A 176 B 177 A 178 A 179 A 180 A 185A 186 A(iii) HT 29 Xenograft in Nude Mouse

5×10⁶ HT29 cells were subcutaneously implanted into the flanks of Balb-cnude mice. Upon reaching approximately 100 mm³, animals were randomisedinto control and treatment groups. Animals were dosed twice per weekwith low dose gemcitabine (10 mg/kg) ie on days 1, 4, 8, and 11, andwhere indicated with compound at its maximum tolerated dose (MTD) 24 and30 hours post the gemcitabine dose. Tumour volume was determined threetimes per week by caliper measurement. Vehicle was dosed instead ofactive ingredient in control animals.

FIG. 1 shows the In vivo potentiation results of the compound of Example20 in combination with gemcitabine. Dosing Schedule: Gemcitabine 10mg/kg i.p. days 1, 4, 8 and 11 (squares) or gemcitabine 10 mg/kg i.p.plus Example 20 at 30 mg/kg i.v. 24 and 30 hours post gemcitabine(triangles). Vehicle (circles) was dosed instead of active ingredient incontrol animals. Tumour volumes were determined by calliper measurement3 times per week.

The invention claimed is:
 1. A method of inhibiting CHK1 activity in amammal, comprising administering to the mammal an amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof effectiveto inhibit CHK1 activity in the mammal:

wherein R₁, R₂, R₅ and R₆ are independently selected from hydrogen,hydroxy, methyl, trifluoromethyl, hydroxymethyl, methoxy,trifluoromethoxy, methylamino and dimethylamino; R₃, and R₄ areindependently selected from hydrogen, hydroxy, C₁-C₃ alkyl,fluoro-(C₁-C₃)-alkyl, hydroxy-(C₁-C₃)-alkyl, C₁-C₃ alkoxy,fluoro-(C₁-C₃)-alkoxy, hydroxy-(C₁-C₃)-alkoxy, —N(R₁₁)—R₁₂,-Alk-N(R₁₁)—R₁₂, —O-Alk-N(R₁₁)—R₁₂, —C(═O)OH, carboxy-(C₁-C₃)-alkyl, orC(═O)—NH—R₁₃; Alk is a straight or branched chain divalent C₁-C₆alkylene radical; R₇ and R₈ are independently selected from hydrogen,hydroxy, or C₁-C₃ alkoxy; X is a straight chain divalent C₁-C₃ alkyleneradical, optionally substituted on one or more carbons by R₉ and/or R₁₀;R₉ and R₁₀ are independently selected from methyl, hydroxy, or fluoro;R₁₁ is hydrogen, C₁-C₃ alkyl, or fluoro-(C₁-C₃)-alkyl, and R₁₂ is C₁-C₃alkyl or hydroxy-(C₁-C₆)-alkyl, either of which may be optionallysubstituted on the alkyl portion by phenyl, C₁-C₃ alkoxy-(C₁-C₃)-alkyl-,halo-(C₁-C₄)-alkyl, C₃-C₆ cycloalkyl, methylsulfonyl-(C₁-C₃)-alkyl or—N(R₁₈)—R₁₉; R₁₃ is hydrogen, C₁-C₃ alkyl, fluoro-(C₁-C₃)-alkyl, or aradical of formula -Alk-N(R₁₄)—R₁₅; R₁₄ and R₁₅ are independentlyselected from hydrogen, C₁-C₃ alkyl, or fluoro-(C₁-C₃)-alkyl; W isselected from —C(═O)—N(—R₁₆)— or —N(—R₁₇)—C(═O)—; R₁₆ or R₁₇ is selectedfrom hydrogen, C₁-C₃ alkyl, or fluoro-(C₁-C₃)-alkyl; R₁₈ and R₁₉ areselected from hydrogen, C₁-C₃ alkyl, or fluoro-(C₁-C₃)-alkyl; Y ishydrogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, or halo; and Q is selected fromoptionally substituted phenyl or optionally substituted cyclohexyl;wherein, unless otherwise defined, “optionally substituted” meansoptionally substituted with at least one substituent selected from(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto,mercapto(C₁-C₆)alkyl, (C₁-C₆)alkylthio, halo, trifluoromethyl,trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, —COOR^(A),—COR^(A), —SO₂R^(A), —CONH₂, —SO₂NH₂, —CONHR^(A), —SO₂NHR^(A),—CONR^(A)R^(B), —SO₂NR^(A)R^(B), —NH₂, —NHR^(A), —NR^(A)R^(B), —OCONH₂,—OCONHR^(A), —OCONR^(A)R^(B), —NHCOR^(A), —NHCOOR^(A), —NR^(B)COOR^(A),—NHSO₂OR^(A), —NR^(B)SO₂OR^(A), —NHCONH₂, —NR^(A)CONH₂, —NHCONHR^(B),—NR^(A)CONHR^(B), —NHCONR^(A)R^(B), or —NR^(A)CONR^(A)R^(B) whereinR^(A) and R^(B) are independently a (C₁-C₆)alkyl group.
 2. The method asclaimed in claim 1 wherein R₃ or R₄ is selected from —N(R₁₁)—R₁₂,-Alk-N(R₁₁)—R₁₂, or —O-Alk-N(R₁₁)—R₁₂, wherein R₁₁ and R₁₂ areindependently selected from methyl and ethyl, or R₁₁ is methyl or ethyland R₁₂ is —N(R₁₈)—R₁₉ wherein R₁₈ and R₁₉ are independently selectedfrom methyl and ethyl.
 3. The method as claimed in claim 1 wherein Alkis —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂C(CH₃)₂CH₂— or is a divalentradical of formula (II):


4. The method as claimed in claim 1 wherein R₁, R₂, R₅ and R₆ are eachhydrogen.
 5. The method as claimed in claim 1 wherein Y is hydrogen ormethyl.
 6. The method as claimed in claim 1 wherein W is—NH—C(═O)—wherein the carbonyl group is linked to the pyrazole ring. 7.The method as claimed in claim 1 wherein R₇ and R₈ are both hydrogen. 8.The method as claimed in claim 1 wherein X is —CH₂—, —CH(CH₃)— or—C(CH₃)₂.
 9. The method as claimed in claim 1 wherein Q is optionallysubstituted phenyl wherein “optionally substituted” means optionallysubstituted with at least one substituent selected from (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto,mercapto(C₁-C₆)alkyl, (C₁-C₆)alkylthio, halo, trifluoromethyl,trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, —COOR^(A),—COR^(A), —SO₂R^(A), —CONH₂, —SO₂NH₂, —CONHR^(A), —SO₂NHR^(A),—CONR^(A)R^(B), —SO₂NR^(A)R^(B), —NH₂, —NHR^(A), —NR^(A)R^(B), —OCONH₂,—OCONHR^(A), —OCONR^(A)R^(B), —NHCOR^(A), —NHCOOR^(A), —NR^(B)COOR^(A),—NHSO₂OR^(A), —NR^(B)SO₂OR^(A), —NHCONH₂, —NR^(A)CONH₂, —NHCONHR^(B),—NR^(A)CONHR^(B), —NHCONR^(A)R^(B), or —NR^(A)CONR^(A)R^(B) whereinR^(A) and R^(B) are independently a (C₁-C₆)alkyl group.
 10. The methodas claimed in claim 9 wherein the substituent or substituents on thephenyl ring is/are selected from methyl, trifluoromethyl, methoxy,fluoro, chloro, or cyano.
 11. The method as claimed in claim 10 whereinQ is 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl,3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 4-methoxy-phenyl,2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 3-chloro-phenyl,4-chloro-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 3,4-difluoro-phenyl,3,5-difluoro-phenyl, or 3-fluoro-4-methyl-phenyl.
 12. The method asclaimed in claim 1 wherein Q is cyclohexyl.
 13. The method as claimed inclaim 1 wherein: R₁, R₂, R₄, R₅, R₆, R₇ and R₈ are each hydrogen; Y ishydrogen or methyl; W is —NH—C(═O)— wherein the carbonyl group is linkedto the pyrazole ring; R₃ is —N(R₁₁)—R₁₂, -Alk-N(R₁₁)—R₁₂, or—O-Alk-N(R₁₁)—R₁₂; R₁₁ and R₁₂ are independently selected from methyland ethyl; or R₁₁ is methyl or ethyl and R₁₂ is —N(R₁₈)—R₁₉ wherein R₁₈and R₁₉ are independently selected from methyl and ethyl; Alk is —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂C(CH₃)₂CH₂— or is a divalent radical offormula (II):

X is —CH₂—, —CH(CH₃)— or —C(CH₃)₂—; and Q is phenyl, optionallysubstituted by one or two substituents selected from C₁-C₃ alkyl,fluoro-(C₁-C₃)alkyl, C₁-C₃ alkoxy, fluoro-(C₁-C₃) alkoxy, halo, andcyano.
 14. The method of claim 1 wherein the compound is selected fromthe group consisting of: 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide,1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(3-dimethylamino-2,2-dimethyl-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide,1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(5-{[(3-dimethylamino-2,2-dimethyl-propyl)-ethyl-amino]-methyl}-1H-indol-2-yl)-6-oxo-1,6-dihydro-pyridin-3-yl]-amide,1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(3-diethylamino-2,2-dimethyl-propoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide,1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide,1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(1-diethylaminomethyl-cyclopropylmethoxy)-1H-indol-2-yl]-6-oxo-1,6-dihydro-pyridin-3-yl}-amide,and a pharmaceutically acceptable salt thereof.